WO2025248139A1 - Use of adrenomedullin or fragments thereof in the treatment of a patient in need thereof - Google Patents

Abstract

Subject matter of the present invention is adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpetidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold. Further subject matter of the present invention is a DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti- ADM binder, in particular an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. A further subject matter of the present invention is an anti-ADM binder, in particular an anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

Description

Use of AdrenomeduUin or fragments thereof in the treatment of a patient in need thereof

Subject matter of the present invention is Adrenomedullin-Gly (ADM-Gly; SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpeptidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold.

Further subject matter of the present invention is a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM binder, in particular an anti- ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

A further subject matter of the present invention is an anti-ADM binder, in particular an anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

State of the Art

AdrenomeduUin (ADM) is one of the best studied peptide hormones, which plays a role in a vast range of physiological and pathophysiological processes, including inter alia vasodilation, angiogenesis, and hormone regulation. ADM is also involved in bronchodilatation, renal function, cell growth, differentiation, neurotransmission, and modulation of the immune response. ADM belongs to the ADM/calcitonin gene-related peptide (CGRP) superfamily of peptides and is known to be produced in various human organs and tissues, including the heart, adrenal endothelial cells, lungs, kidneys, adipose tissue, and vascular endothelium, which contribute to ADM blood levels.

ADM mRNA encodes a preprohormone of 185 amino acids (SEQ ID NO: 1), the pre-pro- Adrenomedullin that is enzymatically converted into Proadrenomedullin by cleavage of the N-terminal signal peptide. Proadrenomedullin (SEQ ID NO: 2) is then further process by several prohormone convertases to result in four peptides, namely

PAMP (SEQ ID NO: 3): Proadrenomedullin amino-terminal peptide or Proadrenomedullin N- terminal 20 peptide with a C-terminal glycine residue,

MR-proADM (SEQ ID NO: 4): Mid-regional Proadrenomedullin, a stable and inert peptide, ADM-Gly (SEQ ID NO: 6): C-terminally glycine extended, inactive precursor of biologically active ADM (mature ADM (SEQ ID NO: 83) and

CT-proADM (SEQ ID NO: 5): C-terminal Proadrenomedullin or Adrenotensin.

ADM-Gly is the direct, inactive biosynthetic precursor of the fully activated ADM form (mature ADM), often referred to as the intermediate form of ADM, and represents the dominating circulating form of ADM in humans. To gain its biological activity, ADM-Gly is activated by the Vitamin C dependent enzyme peptidylglycine-alpha amidating monooxygenase (PAM). PAM recognizes the C-terminal glycine and catalyses a sequential two-step reaction also referred to as amidation or C-terminal amidation.

Mature ADM has several physiological effects, such as vasodilation, angiogenesis, cardioprotection, nephroprotection, anti-oxidation, anti-apoptosis and tissue repair and regeneration. Mature ADM is involved in blood pressure regulation, bronchodilatation, renal function, hormone secretion, cell growth, differentiation, neurotransmission, and modulation of the immune response. Moreover, ADM plays a crucial role as autocrine factor during proliferation and regeneration of endothelial cells.

Additionally, mature ADM promotes angiogenesis, arteriogenesis, prevents cognitive decline after chronic cerebral hypoperfusion and is therefore considered as therapeutic agent in vascular dementia (reviewed in (Garcia et al., 2006) and (Balint et al., 2023).

Dipeptidyl peptidase 3 - also known as Dipeptidyl aminopeptidase III, Dipeptidyl arylamidase III, Dipeptidyl peptidase III, Enkephalinase B or red cell angiotensinase; short name: DPP3, DPPIII - is a metallopeptidase that removes dipeptides from physiologically active peptides, such as enkephalins and angiotensins. DPP3 was identified and its activity measured in extracts of purified bovine anterior pituitary by (Ellis & Nuenke, 1967). The enzyme, which is listed as EC 3.4.14.4, has a molecular mass of about 83 kDa and is highly conserved in procaryotes and eucaryotes (Prajapati & Chauhan, 2011). The amino acid sequence of the human variant is depicted in SEQ ID NO: 70. DPP3 is a mainly cytosolic peptidase which is ubiquitously expressed. Despite lacking a signal sequence, a few studies reported membranous activity (Lee & Snyder, 1982).

DPP3 is a zinc-depending exo-peptidase belonging to the peptidase family M49. It has a broad substrate specificity for oligopeptides from three/ four to ten amino acids of various compositions and is also capable of cleaving after proline. DPP3 is known to hydrolyze dipeptides from the N-terminus of its substrates, including angiotensin II, III and IV; Leu- and Met-enkephalin; endomorphin 1 and 2. The metallopeptidase DPP3 has its activity optimum at pH 8.0-9.0 and can be activated by addition of divalent metal ions, such as Co²⁺ and Mg²⁺.

Structural analysis of DPP3 revealed the catalytic motifs HELLGH (human DPP3 [hDPP3] 450-455) and EECRAE (hDPP3 507-512), as well as following amino acids, that are important for substrate binding and hydrolysis: Glu316, Tyr, 318, Asp366, Asn391, Asn394, His568, Arg572, Arg577, Lys666 and Arg669 (Prajapati & Chauhan, 2011) (Kumar et al., 2016); numbering refers to the sequence of human DPP3, see SEQ ID NO: 70). Considering all known amino acids or sequence regions that are involved in substrate binding and hydrolysis, the active site of human DPP3 can be defined as the area between amino acids 316 and 669. The most prominent substrate of DPP3 is angiotensin II (Ang II), the main effector of the reninangiotensin system (RAS). The RAS is activated in cardiovascular diseases (Dostal et al., 1997) (Roks et al., 1997), sepsis, and septic shock (Correa et al., 2015). Ang II, in particular, has been shown to modulate many cardiovascular functions including the control of blood pressure and cardiac remodeling.

Recently, two assays were generated, characterized, and validated to specifically detect DPP3 in human bodily fluids (e.g., blood, plasma, serum): a luminescence immunoassay (LIA) to detect DPP3 protein concentration and an enzyme capture activity assay (ECA) to detect specific DPP3 activity (Rehfeld et al., 2019). A washing step removes all interfering substances before the actual detection of DPP3 activity is performed. Both methods are highly specific and allow the reproducible detection of DPP3 in blood samples.

Circulating DPP3 (cDPP3) levels were shown to be increased in septic, cardiogenic and vasodilatory shock patients (Rehfeld et al., 2019). Moreover, it was associated with an increased risk of short-term mortality and severe organ dysfunction in patients with cardiogenic shock (Deniau et al., 2020). Moreover, in patients with severe sepsis or septic shock showed that the higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission and the longer the need for vasopressor(s), mechanical ventilation or renal replacement therapy (RRT) and the higher the need for fluid load (Blet et al., 2021).

Thus, efforts have been made to pharmacologically inhibit supranormal concentrations of cDPP3.

Numerous binders that inhibit DPP3 have been described (Abramic & Agic, 2022): Except for the polypeptide aprotinin, all others are small molecules and include flavonoids, coumarin and benzimidazole derivatives. Presented are current strategies for the discovery or development of DPP3 inhibitors, and mechanisms of inhibitory actions. The most potent inhibitors yet reported (propioxatin A and B, Tyr-Phe- and Phe-Phe-NHOH, and JMV-390) are active in low nanomolar range and contain hydroxamic acid moiety. High inhibitory potential possesses oligopeptides from the hemorphin group, valorphin and tynorphin, which are poor substrates of DPP3.

Procizumab, a humanized monoclonal IgGl antibody specifically binding circulating DPP3, targets and modulates the activity DPP3. Its mode of action is relevant in acute diseases that are associated with massive cell death and uncontrolled release of intracellular DPP3 into the bloodstream. Translocated DPP3 remains active in the circulation where it cleaves bioactive peptides in an uncontrolled manner.

Procizumab is able to inhibit circulating DPP3 thereby inhibiting bioactive peptide degradation in the bloodstream. This inhibition results in stabilization of cardiovascular and renal function and reduction of short-term mortality. Preclinical studies of Procizumab in animal models of cardiovascular failure showed impressive and instant efficacy. In several preclinical cardiovascular failure models, Procizumab has shown to normalize ejection fraction and kidney function and reduces mortality (Malovan et al., 2023). Mature ADM as a target and drug-candidate in therapy was investigated in several preclinical and clinical studies. In heart-failure, administration of mature ADM reduced the size of the necrosis zone in myocardial infarction, apoptosis of cardiac myocytes, pronounced remodeling of the left ventricle (in animals), and aldosterone levels (in animals and humans); improvement in hemodynamic parameters (in both humans and animals) and survival (in animals) (see e.g. (NIU et al., 2003) and (Balint et al., 2023). Continuous administration of mature ADM in patients with acute heart failure led to a decrease in mean arterial pressure (MAP), pulmonary artery pressure, systemic and pulmonary vascular resistance, and also led to an increase in cardiac output. In patients with congestive heart failure, infused mature ADM lowered mean arterial pressure and increased heart rate, but to a lower extent when compared to healthy individuals. Mature ADM infusion lowered the pulmonary arterial pressure in heart failure patients, but not in healthy patients. Further, increase in cardiac index was observed, an increase in urine volume and sodium excretion and a decrease in aldosterone levels, both in healthy in patients with HF (reviewed in: (Balint et al., 2023)).

Nothing is known about ADM-Gly as a drug for the treatment of patients, let alone critically ill patients.

In addition, nothing is known about an effect of Adrenomedullin (ADM) and/or related peptides on the activity of DPP3. In the AdrenOSS-2 clinical trial, enibarcimab, a humanized anti-N-terminal Adrenomedullin antibody, has been studied as a drug to treat septic shock patients with elevated predose bio-ADM concentrations (Laterre et al., 2021). A statistically significant interaction between the pre-dose cDPP3 concentration and the treatment effect of enibarcimab was observed: Only upon exclusion of patients with elevated pre-dose cDPP3 concentrations, a beneficial effect of enibarcimab on the 28-day mortality risk of these patients was observed. This was exemplified by employing at cDPP3 cut-off value of 50 ng/mL, and a Cox proportional hazard model predicted a steady relationship between the cDPP3 cut-off applied and the treatment effect of enibarcimab, e.g. the lower the cDPP3 cut-off was chosen for patient inclusion, the stronger the 28-day mortality risk reduction associated with enibarcimab treatment (van Lier et al., 2022).

The analyses by van Lier et al. were further refined and published as an abstract, again from van Lier et al., at the Sepsis update congress, 2023, where even a lower DPP3-cut off of 30 ng/mL was proposed.

If in a subgroup of AdrenOSS-2 defined by having a low pre-dose cDPP3 concentration a much stronger beneficial treatment effect of enibarcimab is observed than in the entire population (full analysis set), it is inherently clear that in the complementary subgroup, e.g. those patients with high pre-dose cDPP3 concentrations, the treatment effect of enibarcimab must be worse than in the entire population. The published data even suggest that treatment with enibarcimab of patients with pathologically elevated pre-dose cDPP3 concentrations could possibly put these patients at risk for increased 28-day mortality compared to placebo. The mechanistic background of this possible adverse effect has been unknown.

The surprising finding of this invention is the effective utilization of mature ADM and/ or ADM-Gly or fragments or modifications thereof as pharmaceutical agents to inhibit DPP3. Moreover, it was the surprising finding of this invention, that a DPP3 binder can be used to treat a patient in need thereof that is to be treated or was treated with an anti-ADM antibody, in particular since the patient may be at risk of having or developing side effects by the pre-treatment with said anti-ADM antibody, if the level of DPP3 in a bodily fluid of said patient is above a threshold.

Furthermore, it was the surprising finding of this invention that an anti-ADM antibody can be used to treat a patient in need thereof that is to be treated or was treated with a DPP3 binder, in particular since the patient may be at risk of having or developing side effects by treatment with an anti-ADM antibody, if the level of DPP3 in a bodily fluid of said patient is above a threshold.

Subject Matter of the Invention

Subject matter of the present invention is Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpeptidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold.

As used herein, the term “for use in the treatment of a patient in need thereof’ can be read as “for use in the treatment of a disease or medical condition in a patient in need thereof’.

According to the invention, ADM-Gly may be selected from the group comprising wildtype ADM-Gly (1-53 ADM) (SEQ ID NO: 6) or a modified form thereof, C-terminally truncated fragments thereof (SEQ ID NO: 7 to 53) or modified forms thereof, and C-terminally truncated fragments thereof with a C-terminal amide-group (SEQ ID NO: 83 to 129) or modified forms thereof.

Fragments of ADM-Gly (SEQ ID NO: 6) have a length of at least 6 amino acids counted from the N- terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group. This means that all fragments under this definition (“i.e. counted from the N-terminus”) comprise the N- terminal amino acid of ADM-Gly.

Modifications of ADM-Gly or fragments thereof as defined herein may be selected from the group comprising:

• Amino acid manipulation, also referred to as site directed mutagenesis, including the insertion, deletion or alteration of one or more amino acids within the polypeptide amino acid sequence, particularly such mutations reducing immunogenicity and proteolytic instability in vivo,

• covalent binding to another moiety, such as (i) an extension by one or more amino acids, or (ii) an extension by a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin,

• covalent binding to a natural or synthetic polymer such as HAP, ELP, PAS, PSA, GLK, carbohydrates, polysaccharides XTEN or PEG, • Non-covalent binding to serum Albumin, e.g. due to a fatty acid chain conjugated to ADM-Gly or a fragment thereof as defined herein. The binding to albumin may therefore occur in vivo after application of the fatty acid conjugated substance and is mediated by the fatty acid chain.

For the avoidance of doubt, particularly, modifications of ADM-Gly or fragments thereof that are extensions by one or more amino acids, insofar as they are C-terminal extensions with amino acids corresponding to the wild type sequence of preproADM, only relate to ADM-Gly (and hence not to fragments of ADM-Gly).

For the avoidance of doubt, particularly, modifications of ADM-Gly or fragments thereof that are deletion of one or more amino acids within the polypeptide amino acid sequence do not include N- terminal deletions (since these are covered by the specific fragments as defined herein). In other words, the term “within the polypeptide amino acid sequence” in particular is to be read as excluding the N- terminal amino acid.

In one embodiment said modification is PEG that is single-stranded or branched PEG, covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof.

In one embodiment said modification is XTEN that is an unstructured polypeptide, covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof. XTEN is a 864 single amino-acid sequence composed of amino-acids Ala, Glu, Gly, Pro, Ser and Thr in a randomized manner. Half-life of an XTEN-fusion protein may be tailored by shortening of the XTEN sequence.

In one embodiment said modification is PAS that is a peptide polymer consisting of amino acids proline, alanine and serine with 100-200 PAS repeats forming the polymer covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof.

In one embodiment said modification is ELP (Elastin-like polypeptides) consisting of Valin-Prolin- Glycine-x-Glycine repeats, naturally found in elastin, wherein x relates to any amino-acid except for Proline covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof.

In one embodiment said modification is HAP that is a repeated sequence of glycine rich (Gly4Ser)n polypeptide, wherein n is in-between of 100-200 and is covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof.

In one embodiment said modification is GLK (gelatin-like fusion protein) is a (Gly-X-Y)n structure, wherein X and Y are any amino-acids except for Cysteine, with n = 60 to 1500 and can be covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments thereof.

In one embodiment said modification are carbohydrates and polysaccharides. Carbohydrates, either branched or linear can be covalently bound to the ADM-Gly (SEQ ID NO: 6) or fragments thereof e.g. through in vivo N-Glycosylation. Conjugation with Dextrans, Hydroxyethyls (HES), Heparosan (HEP), Hyaluronic acid (HA) represents the attachment of polysaccharides. In one embodiment said modification is PSA (Polysialic acid), wherein PSA polymers are covalently bound to ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof.

Fragments of ADM-Gly have a length of at least 6 amino acids counted from the N-terminus of ADM- Gly and wherein said fragments optionally have a C-terminal amide-group. A specific fragment of ADM-Gly is mature ADM (ADM-l-52-amide; SEQ ID NO: 83).

In particular embodiments ADM-Gly (SEQ ID NO: 6) or fragments thereof may be modified with PEG, in particular 1-100 kDa PEG.

In particular embodiments ADM-Gly (SEQ ID NO: 6) or fragments thereof may be modified with albumin, and/or Fc-fragments of IgG’s and/or with XTEN.

Modifications of ADM-Gly or fragments thereof may also include modifications, which allow ADM- Gly or fragments thereof to act as a prodrug. The term "prodrug" denotes a form or derivative of a compound which is metabolized in vivo, e.g., by biological fluids or enzymes by a subject after administration, into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule. The group of the afore mentioned prodrugs comprises Carrier-linked prodrugs (Carrier prodrugs), Cascade prodrugs and PEG-based carrier prodrugs.

A carrier-linked prodrug is a prodrug that contains a temporary linkage of a given active substance with a transient carrier group that produces improved physicochemical or pharmacokinetic properties and that can be easily removed in vivo, usually by a hydrolytic cleavage, wherein a cascade prodrug is a prodrug for which the cleavage of the carrier group becomes effective only after unmasking an activating group and wherein several examples of PEG-based carrier prodrugs exist, most of them with the need for enzymatic activation of the linker between the active drug and the carrier, mostly initiated by enzymatic hydrolysis. Since esters are cleaved very readily and unpredictably in vivo, direct ester linkers for carrier pro drug have limitations to their usability (J. Rautio et al., Nature Reviews Drug discovery, 2008, 7 255-270).

A PEG-based carrier prodrug may refer to a carrier-linked prodrug wherein the carrier group is PEG. In terms of this invention a PEG-based carrier prodrug of ADM-Gly or fragments thereof may mean the addition of a linker structure according to formula 1 to the C-terminus of ADM-Gly or fragments thereof, wherein R1 represents a C-terminal amino acid of ADM-Gly (SEQ ID NO: 6) or fragments thereof (according to SEQ ID NO: 7 to 53, 83 to 129) as indicated in formula 1 and the linker is further conjugated with linear or branched PEG of 1-100 kDa at positions R2 and/or R3 of the linker according to formula 1, and wherein n according to formula 1 may be 1, 2 or 3.

Formula 1

The person skilled in the art is aware that also other forms of prodrugs are known in the art. For examples of such prodrugs see: Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder et al. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs” by H, Bundgaard p. 113-191 (1991); H. Bundgaard, Advanced Drug Delivery Reviews 8, 1-38 (1992); H. Bundgaard, et al.. Journal of Pharmaceutical Sciences, 77, 285 (1988); andN. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

Modified ADM-Gly (SEQ ID NO: 6) or a fragment thereof may be part of a larger molecule, and may be modified by covalent binding to another moiety, wherein said moiety is an extension by one or more amino acids, or a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin, or wherein said moiety is a natural or synthetic polymer, whereas the natural or synthetic polymer to be used is selected from the group comprising HAP, ELP, a carbohydrate, a polysaccharide, PAS, PSA, GLK, XTEN and PEG, preferably ELP, more preferably a carbohydrate, more preferably a polysaccharide, more preferably PAS, more preferably PSA, more preferably GLK, more preferably XTEN and most preferably PEG, or wherein said Adrenomedullin- Gly (SEQ ID NO: 6) or a fragment is modified via non-covalent binding to serum Albumin.

In one embodiment said moiety may be covalently linked directly or indirectly via a linker to Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof.

ADM-Gly or fragments thereof modified via covalent binding to PEG (PEGylation) may refer to ADM- Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 and 83 to 129) modified with 1+n molecules of polyethylene glycol (PEG) at the N-terminus of ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129), whereas n is an integer in the range of 0 to 10 and one PEG molecule has a molecular weight in the range of 1-100 kDa and is either a linear molecule or a branched molecule with b+1 branches, whereas b is an integer in the range of 0 to 20.

In one embodiment said PEG molecule has a molecular weight of 5 kDa, preferably 10 kDa, more preferred 20 kDa, even more preferred 40 kDa, most preferred 60 kDa. ADM-Gly or fragments thereof modified via covalent binding to native serum Albumin or recombinant human serum Albumin may mean ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7-53 and 83-129) covalently bound to native human serum Albumin or recombinant human serum Albumin at the N-terminus of ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129), respectively.

ADM-Gly or fragments thereof modified via covalent binding to IgG Fc regions may refer to ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129) covalently bound to human IgGl Fc Region at the N-terminus of ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129), respectively.

ADM-Gly or fragments thereof modified via XTEN may refer to ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129) covalently bound to a XTEN moiety at the N- terminus of ADM-Gly (SEQ ID NO: 6) or fragments thereof (SEQ ID NO: 7 to 53 or 83 to 129), respectively.

Modifications wherein said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof is part of a larger molecule, may refer to a covalent or non-covalent linkage of said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof to another moiety. A preferred embodiment is covalent linkage of Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof to another moiety.

In a specific embodiment said ADM-Gly fragment is ADM 1-52 (SEQ ID NO: 7) which is N-terminally extended by 1 to 4 amino acids (SEQ ID NO: 130 to 133) or said fragment is ADM 1-52-amide (SEQ ID NO: 83) which is N-terminally extended by 1 to 4 amino acids (SEQ ID N. 134 to 137).

Particularly, extensions of ADG-Gly or fragments thereof are extensions with amino acids that are different from the respective amino acids of the wild-type sequence.

In particular embodiments ADM-Gly or fragments thereof (SEQ ID NO: 7 to 53, 83 to 129) are modified via covalent binding to native serum Albumin or recombinant serum Albumin, preferably modified via covalent binding to IgG Fc regions, more preferably via covalent binding to XTEN, even more preferably via covalent binding to PEG (PEGylation).

Subject matter of the present invention is ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in treatment of a patient in need thereof, wherein said patient has an elevated level DPP3 in the circulation wherein elevated level means that the level of DPP3 in a sample of a bodily fluid of said patient is above a threshold.

The molecular weight of a peptide is defined as the sum of weights (in Dalton) of all atoms in the peptide. Thereby hydrogen has the weight of 1 Da. The molecular weight of mature ADM is 6028.9 Dalton. The molecular weight of ADM-Gly is 6088.9 Dalton. Subject matter of the present invention is ADM-Gly, wildtype ADM-Gly (1-53 ADM) (SEQ ID NO: 6), and/or C-terminal truncated fragments thereof (SEQ ID NO: 7 to 53 and 83 to 129), and/or modified ADM-Gly, modified wildtype ADM-Gly (1-53 ADM) (SEQ ID NO: 6), and/or modified C-terminal truncated fragments thereof (SEQ ID NO: 7 to 53 and 83 to 129) for use in treatment of a patient in need thereof, wherein said patient is characterized by a DPP3 level above a threshold in a sample of bodily fluid of said patient.

In certain embodiments of the invention, the patient is a critically ill patient. “Critically ill” means in particular that said patient is suffering from an acute disease or acute condition which is life-threatening and in which death is possible or imminent. In a specific embodiment said critically ill patient is an ICU patient.

In one embodiment said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure, (iii) a patient undergoing major surgery, (iv) a patient with trauma, (v) a patient with shock and/ or a patient running into shock, or (vi) a patient with cancer optionally receiving an anti-cancer therapy.

In one embodiment said organ dysfunction or organ failure is dysfunction or failure of liver, heart, kidney or lung.

In one embodiment said trauma is trauma bum trauma, polytrauma.

In one embodiment said patient has a shock or is running into shock, wherein said shock is selected from the group comprising shock due to hypovolemia, cardiogenic shock, obstructive shock and distributive shock, in particular cardiogenic shock or septic shock.

In one embodiment said patient has a shock and/ or is running into shock, wherein

• in case of cardiogenic shock said patient may have suffered an acute coronary syndrome (e.g., acute myocardial infarction) or wherein said patient has heart failure (e.g., acute decompensated heart failure), myocarditis, arrhythmia, cardiomyopathy, valvular heart disease, aortic dissection with acute aortic stenosis, traumatic chordal rupture or massive pulmonary embolism, or

• in case of hypovolemic shock said patient may have suffered a hemorrhagic disease including gastrointestinal bleed, trauma, vascular etiologies (e.g., ruptured abdominal aortic aneurysm, tumor eroding into a major blood vessel) and spontaneous bleeding in the setting of anticoagulant use or a non-hemorrhagic disease including vomiting, diarrhea, renal loss, skin losses/insensible losses (e.g., bums, heat stroke) or third-space loss in the setting of pancreatitis, cirrhosis, intestinal obstruction, trauma, or in case of obstructive shock said patient may have suffered a cardiac tamponade, tension pneumothorax, pulmonary embolism or aortic stenosis, or in case of distributive shock said patient may have septic shock, neurogenic shock, anaphylactic shock or shock due to adrenal crisis.

In a preferred embodiment said patient is a patient suffering from heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke.

In another preferred embodiment said patient is a patient suffering from severe infection, sepsis, organ dysfunction or organ failure or shock.

In another preferred embodiment said patient is a patient undergoing major surgery or a patient with trauma.

In yet another preferred embodiment said patient is a patient with shock or a patient running into shock.

In yet another preferred embodiment said patient is a patient with cancer optionally receiving an anticancer therapy.

The threshold according to the present invention may be predetermined by measuring, such as the level of DPP3 in a sample obtained from a cohort of subjects and calculating e.g. the 75th percentile, more particularly the 90th percentile, even more particularly the 95th percentile to define the threshold by which subjects are characterized as suffering from a medical condition or as being at risk of getting a medical condition. In the following examples for thresholds according to the present invention are provided, however, the person skilled in the art is aware on how to determine a specific threshold.

Subject matter according to the invention is ADM-Gly or fragments or modifications thereof for use in treatment of a patient in need thereof, wherein the DPP3 level in a bodily fluid is the DPP3 concentration and/or an enzymatic DPP3 activity.

In one embodiment said threshold of DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL.

In a specific embodiment of the invention said threshold of DPP3 concentration is 120 ng/ml or less, more preferred 100 ng/rnL or less, even more preferred 80 ng/rnL or less, even more preferred 60 ng/ml or less, even more preferred 50 ng/ml or less, most preferred said threshold is 40 ng/mL.

In one embodiment said threshold of enzymatic DPP3 activity is between 50 and 250 U/L, more preferred between 65 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. The DPP3 activity [U/L] was defined and measured as described by (Rehfeld et al., 2019). In a specific embodiment of the invention said threshold of enzymatic DPP3 activity is 250 U/L or less, more preferred 225 U/L or less, even more preferred between 200 U/L or less, most preferred said threshold is 185 U/L.

Subject matter according to the invention is ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a patient in need thereof, wherein ADM-Gly (SEQ ID NO: 6) is administered to said patient at a dosage of 1-1000 pg/kg, preferably 5-750 pg/kg, more preferably 10- 500 pg/kg, more preferably 15-400 pg/kg, more preferably 20-250 pg/kg, most preferred 25-100 pg/kg.

A person skilled in the art knows that for the respective fragments of ADM-Gly (SEQ ID NO: 7-53 and 83 to 129) molar doses corresponding to the dosage for ADM-Gly (SEQ ID NO: 6), adjusted by multiplying the above dosages for ADM-Gly with the fraction of the molecular weight of the fragment divided by the molecular weight of ADM-Gly (i.e MW(fragment)/MW(ADM-Gly)), may be administered to said patient.

In one embodiment of the invention ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof, wherein ADM-Gly (SEQ ID NO: 6) is modified via covalent binding to PEG, wherein the PEG-modified ADM-Gly is administered to said patient at a dosage of 1 to 50 nmol/kg, preferably 2 to 40 nmol/kg, more preferred 3 to 30 nmol/L, even more preferred 4 to 20 nmol/L, even more preferred 5 to 15 nmol/L, most preferred 10 nmol/L.

Further subject matter of the present invention is a pharmaceutical composition for use in the treatment of a patient in need thereof as detailed in the embodiments of the invention, said composition comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof.

In certain embodiments of the invention relating to a pharmaceutical composition for use in the treatment of a patient in need thereof, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof, the level of Dipeptidylpeptidase 3 (DPP3) in a bodily fluid of said patient is above a threshold.

In certain embodiments of the invention relating to a pharmaceutical composition for use in the treatment of a patient in need thereof, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof, said level of DPP3 is the DPP3 concentration (mass per volume) and/or an enzymatic DPP3 activity.

In particular embodiments of the present invention, said pharmaceutical composition is formulated to be administered or is administered orally, epicutaneously, subcutaneously, intradermally, sublingually, intramuscularly, intraarterially, intravenously, via the central nervous system (CNS, intracerebrally, intracerebroventricularly, intrathecally) or via intraperitoneal administration, particularly epicutaneously, subcutaneously, intradermally, intramuscularly, or intraperitoneally, more particularly subcutaneously, intramuscularly, or intraperitoneally; “formulated to be administered (e.g. orally)” likewise reads on “formulated for (e.g. oral) administration”. In the most preferred embodiments of the present invention, said pharmaceutical composition is formulated to be administered or is administered, subcutaneously, intradermally, intramuscularly, intraarterially or intravenously, or via intraperitoneal administration.

According to the present invention the administered dosage might be a single bolus injection delivering the described amount of the compounds to be administered or a continuous infusion of the compounds delivering the desired amount of compounds over a distinct period of time taking into account the velocity of infusion. Thereby the compounds might be administered as a combined injection and/or infusion or as several parallel injections and/or infusion, wherein one or all compounds are delivered as an injection and/or infusions or a distinct compound is injected and another distinct compound is infused.

In certain embodiments of the invention relating to a pharmaceutical composition for use in the treatment of a patient in need thereof as detailed in the embodiments of the invention, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof, said ADM-Gly or fragments thereof is part of a larger molecule, wherein Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof is modified a) by being covalently bound to another moiety, wherein said moiety is (i) an extension by one or more amino acids, or (ii) a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin, or

(iii) a natural or synthetic polymer, whereas the natural or synthetic polymer to be used is selected from the group comprising HAP, ELP, a carbohydrate, a polysaccharide, PAS, PSA, GLK, XTEN and PEG, preferably ELP, more preferably a carbohydrate, more preferably a polysaccharide, more preferably PAS, more preferably PSA, more preferably GLK, more preferably XTEN and most preferably PEG, or b) via non-covalent binding to serum Albumin or c) by amino acid manipulation via site directed mutagenesis, including the insertion, deletion or alteration of one or more amino acids within said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof.

The present invention encompasses a compound or a combination of compounds that is suitable for use in the pharmaceutical industry. This compound includes not only the compound itself, but also a pharmaceutically acceptable salt of the compound and a solvent that is considered safe for pharmaceutical use. It is worth noting that the pharmaceutically acceptable salt and solvate of the compound are not limited to any specific type, but the salt or solvate exemplified above is preferred. The compound, when in the form of a salt or solvate, can be used in various pharmaceutical applications. The compound shall mean ADM-Gly or fragments thereof.

Subject matter of the present invention is a pharmaceutical formulation for use in the treatment of a patient in need thereof as detailed in the embodiments of the invention, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention. In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is a solution, preferably a ready-to- use solution.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is in a freeze-dried state.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is administered intra-muscular.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is administered intra-vascular.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is administered via infusion.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient, comprising ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof according to the present invention, said pharmaceutical formulation is to be administered systemically.

Subject matter of the present invention is ADM-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein said patient is having a level of DPP3 above a threshold.

In one embodiment of the invention said level of DPP3 is the DPP3 concentration (mass per volume) and/or an enzymatic DPP3 activity.

In certain embodiments of the invention relating to ADM-Gly (SEQ ID No. 6) or fragments or derivatives or modifications thereof for use in the treatment of a critically ill patient, said patient has a level of DPP3 in a sample of bodily fluid that is above a threshold when determined by, e.g., immunoassays, activity assays, mass spectrometric methods etc.

DPP3 activity can be measured by detection of cleavage products of DPP3 specific substrates. Known peptide hormone substrates include Leu-enkephalin, Met-enkephalin, endomorphin 1 and 2, valorphin, -casomorphin, dynorphin, proctolin, ACTH (Adrenocorticotropic hormone) and MSH (melanocytestimulating hormone (Abramic et al., 2000) (Barsun et al., 2007) (Dhanda et al., 2008). The cleavage of mentioned peptide hormones as well as other untagged oligopeptides (e.g., Ala-Ala-Ala-Ala, (Dhanda et al., 2008)) can be monitored by detection of the 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), Hl-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 reversed phase chromatography (e.g., (Mazzocco et al., 2006)).

Detection of fluorescence due to hydrolysis of fluorogenic substrates by DPP3 is a standard procedure to monitor DPP3 activity. Those 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) coupled to a fluorophore. Fluorophores include but are not limited to P-naphtylamide (2- naphtylamide, NA, 2NA), 4-methoxy-P-naphtylamide (4-methoxy-2-naphtylamide) and 7-amido-4- methylcoumarin (AMC, MCA; (Abramic et al., 2000) (Ohkubo et al., 1999).

Cleavage of these fluorogenic substrates leads to the release of fluorescent P-naphtylamine or 7-amino- 4-methylcoumarin respectively. In a liquid phase assay or an ECA substrate and DPP3 are incubated in for example a 96 well plate format and fluorescence is measured using a fluorescence detector (Ellis & Nuenke, 1967).

Additionally, DPP3 carrying samples can be immobilized and divided on a gel by electrophoresis, gels stained with fluorogenic substrate (e.g., Arg-Arg-PNA) and Fast Garnet GBC and fluorescent protein bands 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 coupled to chromophores, such as p-nitroanilide diacetate. Detection of color change due to hydrolysis of chromogenic substrates can be used to monitor DPP3 activity.

Another option for the detection of DPP3 activity is a Protease-Gio™ Assay (commercially available at Promega). In this embodiment of said method DPP3 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) are coupled to aminoluciferin. Upon cleavage by DPP3, aminoluciferin is released and serves as a substrate for a coupled luciferase reaction that emits detectable luminescence.

In a preferred embodiment DPP3 activity is measured by addition of the fluorogenic substrate Arg-Arg- PNA and monitoring fluorescence in real time. In another embodiment of the invention, the level of DPP3 is determined by contacting said sample of bodily fluid with a capture binder that binds specifically to DPP3.

In another preferred embodiment of the invention, said capture binder for determining the level of DPP3 may be selected from the group of antibody, antibody fragment or non-IgG scaffold.

In a specific embodiment of the invention, said capture binder for determining the level of DPP3 is an antibody. Another specific embodiment of the invention comprises the use of a capture-binder that binds specifically to full-length DPP3.

In another preferred embodiment of the invention said capture-binder is immobilized on a solid phase. The test sample is passed over the immobilized binder, and DPP3, if present in the sample, binds to the binder and is itself 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. Alternatively, the DPP3 bound to said capture molecule on a solid phase is detected with a second capture molecule specifically binding to DPP3.

For the purposes of the present description, the term "solid phase" may be used to include any material or vessel in which or on which the assay may be performed and includes, but is not limited to porous materials, nonporous materials, test tubes, wells, slides, resins (e.g. magnetic particles, paramagnetic particles, plastics (for example polystyrene, polypropylene, polycarbonate), cyclic olefin copolymers, glass, cellulose, nitrocellulose polyacrylamide, dextran, agarose, metal, or silicone).

In one embodiment of the invention the method for determining DPP3 activity in a bodily fluid sample of said patient comprises the steps:

• contacting said sample with a capture-binder that binds specifically to full-length DPP3,

• separating DPP3 bound to said capture binder,

• adding substrate of DPP3 to said separated DPP3,

• quantifying of said DPP3 activity by measuring and quantifying the conversion of a substrate of DPP3.

In another embodiment of the invention said separation step is a washing step that removes ingredients of the sample that are not bound to said capture-binder from the captured DPP3.

In another embodiment of the invention the DPP3 substrate conversion is detected by a method selected from the group comprising: fluorescence of fluorogenic substrates (e.g. Arg-Arg- NA, Arg-Arg-AMC), color change of chromogenic substrates, luminescence of substrates coupled to aminoluciferin, mass spectrometry, HPLC/ FPLC (reversed phase chromatography, size exclusion chromatography), thin layer chromatography, capillary zone electrophoresis, gel electrophoresis followed by activity staining (immobilized, active DPP3) or western blot (cleavage products).

In another embodiment of the invention said substrate may be selected from the group comprising: angiotensin II, III and IV, Leu-enkephalin, Met-enkephalin, endomorphin 1 and 2, valorphin, 0- casomorphin, dynorphin, proctolin, ACTH and MSH, or di-peptides coupled to a fluorophore, a chromophore or aminoluciferin wherein the di-peptide is Arg-Arg.

In another specific embodiment of the invention said substrate may be selected from the group comprising: A di-peptide coupled to a fluorophore, a chromophore or aminoluciferin wherein the dipeptide is Arg-Arg. In a specific embodiment, said binder exhibits a binding affinity to DPP3 of at least 10⁷ M'¹, preferred 10⁸ M ¹, more preferred affinity is greater than 10⁹ M'¹, most preferred greater than IO¹⁰ M’¹. A person skilled in the art knows that it may be considered to compensate lower affinity by applying a higher dose of compounds and this measure would not lead out-of-the-scope of the invention.

To determine the affinity of the antibodies to DPP3 the kinetics of binding of DPP3 to immobilized antibody was determined by means of label-free surface plasmon resonance using a Biacore 2000 system (GE Healthcare Europe GmbH, Freiburg, Germany). Reversible immobilization of the antibodies was performed using an anti-mouse Fc antibody covalently coupled in high density to a CM5 sensor surface according to the manufacturer's instructions (mouse antibody capture kit; GE Healthcare), (Lorenz et al., 2011).

In one embodiment such assay for determining the concentration (mass per volume) of DPP3 is a sandwich immunoassay using any kind of detection technology including but not restricted to enzyme label, chemiluminescence label, electrochemiluminescence label, preferably a fully automated assay. In one embodiment of the diagnostic method such an assay is an enzyme labeled sandwich assay. Examples of automated or fully automated assay comprise assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Advia Centauer®, Siemens Immulite ®, Brahms Kryptor®, Biomerieux Vidas®, Alere Triage®, Boditech AFIAS®, Ortho Vidas®, Diasorin LIASION®, Beckman Dxl®, Lumira Dx®, MeMed Key®, Werfen BioFlash®, BioRad BioPlex®.

A variety of immunoassays are known and may be used for the assays and methods of the present invention, these include: mass spectrometry (MS), luminescence immunoassay (LIA), radioimmunoassays ("RIA"), homogeneous enzyme-multiplied immunoassays ("EMIT"), enzyme linked immunoadsorbent assays ("ELISA"), apoenzyme reactivation immunoassay ("ARIS"), chemiluminescence- (“CLIA”), electrochemiluminescence- (“ECLIA”) and fluorescenceimmunoassays, luminescence-based bead arrays, magnetic beads based arrays, protein microarray assays, rapid test formats such as for instance dipstick immunoassays, immuno-chromatographic strip tests, rare cryptate assay and automated systems/ analyzers.

In one embodiment of the invention, it may be a so-called POC-test (point-of-care) that is a test technology, which allows performing the test within less than 1 hour near the patient without the requirement of a fully automated assay system. One example for this technology is the immunochromatographic test technology, e.g., a microfluidic device.

In a specific embodiment at least one of said two binders is labeled in said sandwich immunoassay in order to be detected.

In another preferred embodiment said label is selected from the group comprising chemiluminescent label, enzyme label, fluorescence label, radioiodine label. The assays can be homogenous or heterogeneous assays, competitive and non-competitive assays. In one embodiment, the assay is in the form of a sandwich assay, which is a non-competitive immunoassay, wherein the molecule to be detected and/or quantified is bound to a first antibody and to a second antibody.

The first antibody may be bound to a solid phase, e.g. a bead, a surface of a well or other container, a chip or a strip, and the second antibody is an antibody which is labeled, e.g. with a dye, with a radioisotope, or a reactive or catalytically active moiety. The amount of labeled antibody bound to the analyte is then measured by an appropriate method. The general composition and procedures involved with “sandwich assays” are well-established and known to the skilled person (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(l):4-10. PMID: 16376134).

In another embodiment the assay comprises two capture molecules, preferably antibodies which are both present as dispersions in a liquid reaction mixture, wherein a first labelling component is attached to the first capture molecule, wherein said first labelling component is part of a labelling system based on fluorescence- or chemiluminescence-quenching or amplification, and a second labelling component of said marking system is attached to the second capture molecule, so that upon binding of both capture molecules to the analyte a measurable signal is generated that allows for the detection of the formed sandwich complexes in the solution comprising the sample.

In another embodiment, said labeling system comprises rare earth cryptates or rare earth chelates in combination with fluorescence dye or chemiluminescence dye, in particular a dye of the cyanine type.

In the context of the present invention, fluorescence-based assays comprise the use of dyes, which may for instance be selected from the group comprising FAM (5-or 6-carboxyfluorescein), VIC, NED, Fluorescein, Fluoresceinisothiocyanate (FITC), IRD-700/800, Cyanine dyes, such as CY3, CY5, CY3.5, CY5.5, Cy7, Xanthen, 6-Carboxy-2’,4’,7’,4,7-hexachlorofluorescein (HEX), TET, 6-Carboxy-4’,5’- dichloro-2’,7’-dimethodyfluorescein (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, Oregon Green, Coumarines such as Umbelliferone, Benzimides, such as Hoechst 33258; Phenanthridines, such as Texas Red, Yakima Yellow, Alexa Fluor, PET, Ethidiumbromide, Acridinium dyes, Carbazol dyes, Phenoxazine dyes, Porphyrine dyes, Polymethin dyes, and the like.

In the context of the present invention, chemiluminescence based assays comprise the use of dyes, based on the physical principles described for chemiluminescent materials in (Kirk-Othmer, Encyclopedia of chemical technology, 4th ed., executive editor, J. I. Kroschwitz; editor, M. Howe-Grant, John Wiley & Sons, 1993, vol.!5,p. 518-562, incorporated herein by reference, including citations on pages 551-562). Preferred chemiluminescent dyes are acridiniumesters. As mentioned herein, an “assay” or “diagnostic assay” can be of any type applied in the field of diagnostics. Such an assay may be based on the binding of an analyte to be detected to one or more capture probes with a certain affinity. Concerning the interaction between capture molecules and target molecules or molecules of interest, the affinity constant is preferably greater than 10⁸ M ¹.

In certain embodiments of the invention relating to ADM-Gly (SEQ ID No. 6) or fragments or derivatives or modifications thereof for use in the treatment of a critically ill patient, said threshold of DPP3 concentration (mass per volume) is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL.

In a specific embodiment an assay is used for determining the level of DPP3, wherein the assay sensitivity of said assay is able to quantify the DPP3 of healthy subjects and is < 20 ng/ml, preferably < 30 ng/ml and more preferably < 40 ng/ml.

In certain embodiments of the invention relating to ADM-Gly (SEQ ID No. 6) or fragments or derivatives or modifications thereof for use in the treatment of a critically ill patient, wherein said threshold of enzymatic DPP3 activity is between 50 and 250 U/L, more preferred between 65 and 225 UZL, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L.

A bodily fluid according to the present invention is in one particular embodiment a blood sample. A blood sample may be selected from the group comprising whole blood, serum and plasma. In a specific embodiment of the method said sample is selected from the group comprising human citrate plasma, heparin plasma and EDTA plasma.

In another specific embodiment of the present invention said level of DPP3 is determined in different samples taken from said patient at different time-points. In another specific embodiment of the present invention the difference between said level of DPP3 in different samples taken from said patient at different time-points is determined. The difference may be determined as absolute or relative difference.

In a specific embodiment of the present invention said level of DPP3 is determined at least twice.

In another specific embodiment of the present invention a therapy is initiated when said relative difference between said level of DPP3 in different samples taken from said patient at different timepoints is 100% or above, more preferred 75% or above, even more preferred 50% or above, most preferred 25% or above.

In another specific embodiment of the present invention said at least second determination of the level of DPP3 is conducted within 2 hours, preferably within 4 hours, more preferred within 6 hours, even more preferred within 12 hours, even more preferred within 24 hours, most preferred within 48 hours.

The level of DPP3 as the DPP3 concentration (mass per volume) and/ or DPP3 activity in a sample of bodily fluid of said subject may be determined for example by one of the following methods: 1. Luminescence immunoassay for the quantification of DPP3 protein concentrations (LIA) (Rehfeld et al., 2019).

The LIA is a one-step chemiluminescence sandwich immunoassay that uses white high-binding polystyrene microtiter plates as solid phase. These plates are coated with monoclonal anti-DPP3 antibody AK2555 (capture antibody).

The tracer anti-DPP3 antibody AK2553 is labeled with MA70-acridinium-NHS-ester and used at a concentration of 20 ng per well. Twenty microliters of samples (e.g., serum, heparin-plasma, citrate- plasma or EDTA-plasma derived from patients’ blood) and calibrators are pipetted into coated white microtiter plates. After adding the tracer antibody AK2553, the microtiter plates are incubated for 3 h at room temperature and 600 rpm. Unbound tracer is then removed by 4 washing steps (350 pL per well). Remaining chemiluminescence is measured for 1 s per well by using a microtiter plate luminometer. The concentration of DPP3 is determined with a 6-point calibration curve. Calibrators and samples are preferably run in duplicate.

2. Enzyme capture activity assay for the quantification of DPP3 activity (ECA) (Rehfeld et al., 2019).

The ECA is a DPP3 -specific activity assay that uses black high-binding polystyrene microtiter plates as solid phase. These plates are coated with monoclonal anti-DPP3 antibody AK2555 (capture antibody). Twenty microliters of samples (e.g., serum, heparin-plasma, citrate-plasma, EDTA-plasma, cerebrospinal fluid and urine) and calibrators are pipetted into coated black microtiter plates. After adding assay buffer (200 pL), the microtiter plates are incubated for 2 h at 22°C and 600 rpm. DPP3 present in the samples is immobilized by binding to the capture antibody. Unbound sample components are removed by 4 washing steps (350 pL per well). The specific activity of immobilized DPP3 is measured by the addition of the fluorogenic substrate, Arg-Arg-0-Naphthylamide (Arg2- NA), in reaction buffer followed by incubation at 37 °C for 1 h. DPP3 specifically cleaves Arg2-0NA into Arg- Arg dipeptide and fluorescent -naphthylamine. Fluorescence is measured with a fluorometer using an excitation wavelength of 340 nm and emission is detected at 410 nm. The activity of DPP3 is determined with a 6-point calibration curve. Calibrators and samples are preferably run in duplicates.

3. Liquid-phase assay for the quantification of DPP3 activity (LAA) (modified from (Jones & Kapralou, 1982)).

The LAA is a liquid phase assay that uses black non-binding polystyrene microtiter plates to measure DPP3 activity. 20 pl of samples (e.g., serum, heparin-plasma, citrate-plasma) and calibrators are pipetted into non-binding black microtiter plates. After addition of fluorogenic substrate, Arg2-0NA, in assay buffer (200 pL), the initial 0NA fluorescence (T=0) is measured in a fluorimeter using an excitation wavelength of 340 nm and emission is detected at 410 nm. The plate is then incubated at 37 °C for 1 hour. The final fluorescence of (T=60) is measured. The difference between final and initial fluorescence is calculated. The activity of DPP3 is determined with a 6-point calibration curve. Calibrators and samples are preferably run in duplicates.

The DPP3 levels of the present invention have been determined with the described DPP3 -assays as outlined in the examples (Rehfeld et al., 2019). The mentioned threshold values above might be different in other assays, if these have been calibrated differently from the assay systems used in the present invention. Therefore, the mentioned cut-off values above shall apply for such differently calibrated assays accordingly, taking into account the differences in calibration. One possibility of quantifying the difference in calibration is a method comparison analysis (correlation) of the assay in question with the respective biomarker assay used in the present invention by measuring the respective biomarker (e.g., DPP3) in samples using both methods. Another possibility is to determine with the assay in question, given this test has sufficient analytical sensitivity, the median biomarker level of a representative normal population, compare results with the median biomarker levels as described in the literature and recalculate the calibration based on the difference obtained by this comparison. With the calibration used in the present invention, samples from 5,400 normal (healthy) subjects (Swedish single-center prospective population-based Study (MPP-RES)) have been measured: median (interquartile range) plasma DPP3 was 14.5 ng/ml (11.3 ng/ml - 19 ng/ml).

Threshold levels can be obtained for instance from a Kaplan-Meier analysis, where the occurrence of a disease is correlated with the quartiles of the biomarker in the population. According to this analysis, subjects with biomarker levels above the 75th percentile have a significantly increased risk for getting the diseases according to the invention. This result is further supported by Cox regression analysis with full adjustment for classical risk factors: The highest quartile versus all other subjects is highly significantly associated with increased risk for getting a disease according to the invention.

Other preferred cut-off values are for instance the 90th, 95th or 99th percentile of a normal population. By using a higher percentile than the 75th percentile, one reduces the number of false positive subjects identified, but one might miss to identify subjects, who are at moderate, albeit still increased risk. Thus, one might adopt the cut-off value depending on whether it is considered more appropriate to identify most of the subjects at risk at the expense of also identifying "false positives", or whether it is considered more appropriate to identify mainly the subjects at high risk at the expense of missing several subjects at moderate risk.

Subject matter of the present invention is a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

In certain embodiment, the DPP3 binder is an inhibitor of DPP3 activity. Inhibitors are molecules that preferably significantly inhibit DPP3 activity. Those molecules can be peptides and small molecules, antibodies, antibody fragments or non-Ig scaffolds. Significantly inhibiting means in particular inhibiting the activity of DPP3 more than 10%, preferably more than 20%, more preferably more than 30%, even more preferred more than 40%, even more preferred more than 50%, even more preferred more than 60%, even more preferably more than 70%, even more preferably more than 80 %, even more preferably more than 90 %, even more preferably about or actually 100% inhibition.

For the avoidance of doubt, this means that less than 90%, preferably less than 80%, more preferably less than 70%, even more preferred less than 60%, even more preferred less than 50%, even more preferred less than 40%, even more preferred less than 30%, even more preferably less than 20 %, even preferably less than 10 %, even more preferably about or actually 0% of DPP3 activity remain.

The activity of DPP3 can be inhibited unspecifically by different general protease inhibitors (e.g., PMSF, TPCK), sulfhydryl reagents (e.g., pHMB, DTNB) and metal chelators (EDTA, o-phenantroline) (Abramic et al. 2000. Biological Chemistry, 381: 1233-1243; EP 2949332) .

DPP3 activity can be further inhibited specifically by different kinds of compounds: an endogenous DPP3 -inhibitor is the peptide spinorphin. Several synthetic derivatives of spinorphin, e.g., tynorphin, have been produced and shown to inhibit DPP3 activity to varying extents (Yamamoto et al. 2000. Life sciences 62 (19): 1767-1773). Other published peptide inhibitors of DPP3 are propioxatin A and B (US 4804676) and propioxatin A analogues (Inaoka et al. 1988. J. Biochem 104 (5): 706-711).

A „derivative or analogue¹⁴ is a chemical compound that is derived from a parent compound by a chemical reaction with the replacement of one atom or substitution of a group of atoms by a functional group. Parent and derivative compounds have similar chemical structures.

DPP3 can also be inhibited by small molecules such as fluostatins and benzimidazol derivatives. Fluostatins A and B are antibiotics produced in Streptomyces sp. TA-3391 that are non-toxic and strongly inhibit DPP3 activity. So far, 20 different derivatives of benzimidazol have been synthesized and published (Agic et al. 2007. Bioorganic Chemistry 35 (2); 153-169; Rastija et al. 2015. Acta Chimica Slovenica 62; 867-878). of which the two compounds 1’ and 4’ show the strongest inhibitory effect (Agic et al. 2007. Bioorganic Chemistry 35 (2); 153-169). Several dipeptidyl hydroxamic acids have been shown to inhibit DPP3 activity as well (Cvitesic et al., 2016. J Enzyme Inhib Med Chem 31(sup2):40-45).

A “small molecule” is in particular a low molecular weight (more particularly < 1000 daltons) organic compound. Such small molecules may in particular regulate a biological process, e.g. bind a specific biological macromolecule, in the present invention in particular DPP3, and act as an effector, in particular an inhibitor, altering the activity or function of the biological macromolecule.

Particular examples of small molecule and peptide inhibitors of DPP3 are shown in the following Table 1. Compounds 1’ and 4’ show the strongest inhibitory effect (Agic et al. 2007).

Table 1: Peptide and small molecule inhibitors of DPP3.

In certain embodiments of the invention relating to a DPP3 binder for for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, the DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibody, anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold.

In one embodiment of the invention the DPP3 binder is a small molecule selected from the group comprising spinorphin, tynorphin, propioxatin A and B, fluostatin A and B, enzimidazole or derivatives or analogues thereof.

In another embodiment of the invention said binder is an anti-DPP3 antibody, anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold.

In one embodiment said anti-DPP3 antibody, anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold exhibits a minimum binding affinity to full-length DPP3 of equal or less than 10'⁷ M.

In one embodiment said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment.

Throughout the specification the “antibodies”, or “antibody fragments” or “non-Ig scaffolds” in accordance with the invention are capable to bind DPP3, and thus are directed against DPP3, and thus can be referred to as “anti-DPP3 antibodies”, “anti-DPP3 antibody fragments”, or “anti-DPP3 non-Ig scaffolds”.

The term “antibody” generally comprises monoclonal and polyclonal antibodies and binding fragments thereof, in particular Fc-fragments as well as so called “single-chain-antibodies” (Bird et al. 1988), chimeric, humanized, in particular CDR-grafted antibodies, and dia- or tetrabodies (Holliger et al. 1993). Also comprised are immunoglobulin-like proteins that are selected through techniques including, for example, phage display to specifically bind to the molecule of interest contained in a sample. In this context the term “specific binding” refers to antibodies raised against the molecule of interest or a fragment thereof. An antibody is considered to be specific, if its affinity towards the molecule of interest or the aforementioned fragment thereof is at least preferably 50-fold higher, more preferably 100-fold higher, most preferably at least 1000-fold higher than towards other molecules comprised in a sample containing the molecule of interest. It is well known in the art how to make antibodies and to select antibodies with a given specificity. In one embodiment of the invention the anti-DPP3 antibody or anti-DPP3 antibody fragment or anti- DPP3 non-Ig scaffold is monospecific.

Monospecific anti-DPP3 antibody or monospecific anti-DPP3 antibody fragment or monospecific anti- DPP3 non-Ig scaffold means that said antibody or antibody fragment or non-Ig scaffold binds to one specific region encompassing at least 5 amino acids within the target DPP3 (SEQ ID NO: 70). Monospecific anti-DPP3 antibody or monospecific anti-DPP3 antibody fragment or monospecific anti- DPP3 non-Ig scaffold are anti-DPP3 antibodies or anti-DPP3 antibody fragments or anti-DPP3 non-Ig scaffolds that all have affinity for the same antigen. Monoclonal antibodies are monospecific, but monospecific antibodies may also be produced by other means than producing them from a common germ cell.

In a specific embodiment said anti-DPP3 antibody, anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold is an inhibiting antibody, fragment or non-Ig scaffold. Said anti-DPP3 antibody, anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold is inhibiting the activity of DPP3 more than 10%, preferably more than 20%, more preferably more than 30%, even more preferred more than 40%, even more preferred more than 50%, even more preferred more than 60%, even more preferably more than 70%, even more preferably more than 80 %, even more preferably more than 90 %, even more preferred more than 95%, even more preferably almost or actually 100%. For the avoidance of doubt, this means that less than 90%, preferably less than 80%, more preferably less than 70%, even more preferred less than 60%, even more preferred less than 50%, even more preferred less than 40%, even more preferred less than 30%, even more preferably less than 20 %, even preferably less than 10 %, even more preferably about or actually 0% of DPP3 activity remain.

An antibody or fragment according to the present invention is a protein including one or more polypeptides substantially encoded by immunoglobulin genes that specifically binds an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha (IgA), gamma (IgGi, IgGi, IgGs, IgG₄), delta (IgD), epsilon (IgE) and mu (IgM) constant region genes, as well as the myriad immunoglobulin variable region genes. Full-length immunoglobulin light chains are generally about 25 Kd or 214 amino acids in length.

Full-length immunoglobulin heavy chains are generally about 50 Kd or 446 amino acids in length. Light chains are encoded by a variable region gene at the NFh-terminus (about 110 amino acids in length) and a kappa or lambda constant region gene at the COOH-terminus. Heavy chains are similarly encoded by a variable region gene (about 116 amino acids in length) and one of the other constant region genes.

The basic structural unit of an antibody is generally a tetramer that consists of two identical pairs of immunoglobulin chains, each pair having one light and one heavy chain. In each pair, the light and heavy chain variable regions bind to an antigen, and the constant regions mediate effector functions. Immunoglobulins also exist in a variety of other forms including, for example, Fv, Fab, and (Fab')2, as well as bifunctional hybrid antibodies and single chains (e.g., (Lanzavecchia & Scheidegger, 1987) (Huston et al., 1988) (Bird et al., 1988) Hood et al. 1984, Immunology, Beniamin, N.Y, ²ⁿd ed.; Hunkapiller and Hood 1986. Nature 323:15-16). An immunoglobulin light or heavy chain variable region includes a framework region interrupted by three hypervariable regions, also called complementarity determining regions (CDR's) (see, Sequences of Proteins of Immunological Interest, E. Kabat et al. 1983, U.S. Department of Health and Human Services . As noted above, the CDRs are primarily responsible for binding to an epitope of an antigen. An immune complex is an antibody, such as a monoclonal antibody, chimeric antibody, humanized antibody or human antibody, or functional antibody fragment, specifically bound to the antigen.

Chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin variable and constant region genes belonging to different species. For example, the variable segments of the genes from a mouse monoclonal antibody can be joined to human constant segments, such as kappa and gamma 1 or gamma 3. In one example, a therapeutic chimeric antibody is thus a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody, although other mammalian species can be used, or the variable region can be produced by molecular techniques. Methods of making chimeric antibodies are well known in the art, e.g., see U.S. Patent No. 5,807,715. A "humanized" immunoglobulin is an immunoglobulin including a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin. The non-human immunoglobulin providing the CDRs is termed a "donor" and the human immunoglobulin providing the framework is termed an "acceptor". In one embodiment, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, i.e., at least about 85- 90%, such as about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences. A "humanized antibody" is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin.

A humanized antibody binds to the same antigen as the donor antibody that provides the CDR’s. 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 can have additional conservative amino acid substitutions, which have substantially no effect on antigen binding or other immunoglobulin functions.

Exemplary conservative substitutions are those such as gly, ala; val, ile, leu; asp, glu; asn, gin; ser, thr; lys, arg; and phe, tyr. Humanized immunoglobulins can be constructed by means of genetic engineering (e.g., see U.S. Patent No. 5,585,089). A human antibody is an antibody wherein the light and heavy chain genes are of human origin. Human antibodies can be generated using methods known in the art. Human antibodies can be produced by immortalizing a human B cell secreting the antibody of interest. Immortalization can be accomplished, for example, by EBV infection or by fusing a human B cell with a myeloma or hybridoma cell to produce a trioma cell. Human antibodies can also be produced by phage display methods (see, e.g., WO91/17271; WQ92/001047; WO92/2Q791}, or selected from a human combinatorial monoclonal antibody library (Choi et al., 2023) ). Human antibodies can also be prepared by using transgenic animals carrying a human immunoglobulin gene (for example, see WO93/12227; WO 91/10741}.

Methods for obtaining monoclonal antibodies

In all of the following embodiments, the term monoclonal antibody is meant to include monoclonal antibodies, as well as fragments of monoclonal antibodies, such as the ones detailed herein, more particularly monoclonal antibodies.

Hybridoma

In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) fusing antibody-secreting cells from an animal previously immunized with an antigen with myeloma cells to obtain a multitude of hybridomas, ii) isolating from said multitude of hybridomas a hybridoma producing a desired monoclonal antibody.

In certain embodiments, the antibody according to the present invention is a monoclonal antibody obtainable by isolating from a multitude of hybridomas a hybridoma producing a desired monoclonal antibody, wherein said multitude of hybridomas were produced by fusing antibody-secreting cells from an animal previously immunized with an antigen with myeloma cells to obtain multitude of hybridomas. A desired monoclonal antibody is in particular a monoclonal antibody binding the antigen, in particular with a binding affinity of at least 10⁷ M’¹, preferred 10⁸ M ¹, more preferred affinity is greater than 10⁹ M’¹, most preferred greater than IO¹⁰ M ¹.

In certain embodiments of the method for obtaining an antibody, in step i) the animal is a mammal, particularly a rabbit, a mouse or a rat, more particularly a mouse, more particularly a Balb/c mouse.

In certain embodiments of the method for obtaining an antibody, in step i) the antibody-secreting cell is a splenocyte, more particularly an activated B-cell.

In certain embodiments of the method for obtaining an antibody, in step i) fusing involves the use of polyethylene glycol.

In certain embodiments of the method for obtaining an antibody, in step i) the myeloma is derived from a mammal, in certain embodiments from the same species of mammal from which the multitude of antibody-secreting cells is obtained. In certain specific embodiments of the method for obtaining an antibody, in step i) the myeloma cells are of the cell line SP2/0.

In certain embodiments of the method for obtaining an antibody, said fusing in step i) comprises PEG- assisted fusion, Sendai virus-assisted fusion or electric current-assisted fusion. In certain embodiments of the method for obtaining an antibody, said isolating in step ii) comprises performing an antibody capture assay, an antigen capture assay, and/or a functional screen.

In certain embodiments of the method for obtaining an antibody, in step ii) isolating the hybridoma producing a desired monoclonal antibody may involve cloning and re-cloning the hybridomas using the limiting-dilution technique.

In one embodiment, said antigen capture assay comprises: a) binding the produced antibodies to a substrate, particularly a solid substrate, b) allowing antigen to bind to said antibodies, c) removing unbound antigen by washing, d) detecting bound antigen; or said antigen capture assay comprises: a) allowing an antigen to bind the produced antibodies to form an antibody-antigen complex, b) binding said antibody-antigen complex to a substrate, particularly a solid substrate, c) removing unbound antigen by washing, d) detecting bound antigen.

In one embodiment, said isolating of step ii) comprises performing an enzyme-linked immunosorbent assay, fluorescence-activated cell sorting, cell staining, immunoprecipitation, and/or a western blot.

In one embodiment, said detecting of the antibody or the antigen is accomplished with an immunoassay. In one embodiment, the animal is a transgenic animal, in particular a transgenic mouse (wherein in particular the mouse immunoglobulin (Ig) gene loci have been replaced with human loci within the transgenic animal genome), such as HuMabMouse or XenoMouse.

In one embodiment, the antigen comprises a peptide as described herein in Table 2, which in certain embodiments (in particular for immunization) may be conjugated to a protein, particularly a serum protein, more particularly a serum albumin, more particularly BSA.

In a preferred embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) fusing splenocytes cells from a Balb/c mouse previously immunized with a peptide as described herein in Table 2 with SP2/0 myeloma cells using polyethylene glycol, to obtain a multitude of hybridomas, ii) isolating from said multitude of hybridomas a hybridoma producing a desired monoclonal antibody; more preferably, the method comprises:

1) growing hybridomas for a first period (in particular 2 weeks) in HAT medium [RPMI 1640 culture medium supplemented with 20% fetal calf serum and HAT-Supplement]

2) followed replacing HAT medium with HT Medium for a multitude of passages (in particular 3) 3) followed by returning to the normal cell culture medium for a second time period, in particular until the end of three weeks after fusion

4) primary screening of cell culture supernatants for antigen-specific IgG antibodies

5) propagating microcultures of cells that tested positive in 4)

6) retesting cell culture supernatants of microcultures for antigen-specific IgG antibodies

7) cloning and re-cloning cultures that tested positive in 6), using the limiting-dilution technique

8) optionally determining the isotypes of clones obtained from 7)

9) optionally purifying antibodies via Protein A

Phage Display

In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) isolating at least one antibody having affinity to an antigen from an antibody gene library; ii) generating at least one cell strain expressing said at least one antibody; iii) isolating the at least one antibody from a culture of the at least one cell strain obtained in step ii).

An antibody having affinity to an antigen is in particular an antibody with a binding affinity of at least 10⁷ M ¹, preferred 10⁸ M ¹, more preferred affinity is greater than 10⁹ M’¹, most preferred greater than IO¹⁰ M’¹.

In a certain embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by isolating at least one antibody from a culture derived from at least one cell strain which expressed at least one antibody having affinity to an antigen from an antibody gene library.

In one embodiment, the antigen comprises a peptide as described herein in Table 2, which in certain embodiments may be bound to a solid phase.

In certain embodiments of the method for obtaining an antibody, in step i) the antibody gene library is a naive antibody gene library, particularly a human naive antibody gene library, more particularly in said library the antibodies are presented via phage display, i.e. on phages comprising a nucleotide sequence encoding for such respective antibody; more particularly the library HAL 7, HAL 8, or HAL 9, more particularly a library comprising the human naive antibody gene libraries HAL7/8.

In certain embodiments of the method for obtaining an antibody, in step i) screening comprises the use of an antigen, particularly an antigen containing a tag, more particularly a biotin tag, linked thereto via two different spacers. In particular embodiments, such panning strategy includes a mix of panning rounds with non-specifically bound antigen and antigen bound specifically via the tag, in the case of a biotin tag, bound to streptavidin. In this way, the background of non-specific binders may be minimized. In certain embodiments of the method for obtaining an antibody, in step i), in embodiments wherein the library is a phage display library, the antibody is isolated by isolating a phage presenting said antibody (and comprising a nucleotide sequence encoding for the antibody).

In certain embodiments of the method for obtaining an antibody, in step ii) said cell strain is generated via introduction of a nucleotide sequence encoding for the antibody), in embodiments wherein the library in step i) is a phage display library, the isolated phage from step i) may be used to produce a bacterial strain, e.g. an E. coli strain, expressing the antibody.

In certain embodiments of the method for obtaining an antibody, in step iv); in embodiments wherein the library in step i) is a phage display library and wherein a bacterial strain is produced in step ii), antibody may be isolated from the supernatant of the culture.

It is understood that, as used in describing the methods for obtaining an antibody, the term “one antibody” in the expression “at least one antibody” in particular may include more than one antibody molecule of antibodies having the same amino acid sequence. This understanding applies, mutatis mutandis, to the term “one cell strain”.

In certain embodiments of the method for obtaining an antibody, more than one antibody (referring to a multitude of antibodies having distinct amino acid sequences, respectively) is isolated in step i) and accordingly more than one cell strain is generated in step ii). Such method may involve the selection of clones that are positive for binding to the antigen, e.g. via a binding assay, e.g. an ELISA assay involving the antigen, and cells positive for binding to the antigen may be isolated to produce monoclonal cell strains.

In a preferred embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) isolating at least one antibody having affinity to an antigen from an antibody gene library comprising the human naive antibody gene libraries HAL7/8, by eluting phages carrying said antibody from the library; ii) generating at least one E. coli cell strain expressing said at least one antibody; iii) isolating the at least one antibody from the supernatant a culture of the at least one E. coli cell strain obtained in step ii).

In a further aspect, an antibody fragment according to the present invention is produced by a method in volving enzymatic digestion of an antibody.

In certain embodiments, this method produces e.g. Fab or F(ab)2 antibody fragments. In certain embodiments, this method involves digestion with pepsin or papain, which are optionally immobilized on a surface.

In certain embodiments, antibodies may be humanized by CDR-grafting, in particular by a process involving the steps: - extracting RNA from hybridomas expressing an antibody of interest (e.g. obtained by a method as described herein);

- amplifying said extracted RNA via RT-PCR, in particular with primer sets specific for the heavy and light chains of the antibody of interest, to obtain to obtain a DNA product;

- further amplifying said DNA product via PCR, in particular using semi-nested primer sets specific for antibody variable regions;

- determining the sequence of the DNA product;

- aligning said sequence with homologous human framework sequences to determine a humanized sequence for the variable heavy chain and the variable light chain sequences (of the desired antibody).

In certain embodiments, antibodies may be humanized by aligning the sequence of a DNA product that was obtained by amplifying RNA extracted from hybridomas expressing an antibody of interest via RT- PCR, in particular with primer sets specific for the heavy and light chains of the antibody of interest and further amplifying the DNA obtained therefrom via PCR, in particular using semi-nested primer sets specific for antibody variable regions, with homologous human framework sequences to determine a humanized sequence for the variable heavy chain and the variable light chain sequences (of the desired antibody).

In certain embodiments, antibodies may be humanized by

- determining the complementary determining regions (CDR), which may be accomplished by analysing the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen;

- transplanting said CDR sequences into a human framework region.

In certain embodiments, antibodies may be humanized by transplanting CDR sequences, which may preferably have been determined by analysing the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen, into a human framework region.

In certain embodiments variations in the amino acid sequence of the CDRs or FRs may be introduced to maintain structural interactions with the antigen (which may otherwise be abolished by introducing the human FR sequences), for instance by a random approach using phage display libraries or via directed approach guided by molecular modelling.

The DNA sequences encoding for antibodies determined as detailed herein can be transferred by known genetic engineering techniques into cells and used for production of the antibody.

Producing antibodies

In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by a method comprising: culturing a cell strain comprising a nucleotide sequence encoding for the antibody; isolating the antibody from said culture. In a further certain aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by isolating the antibody from a culture of a cell strain comprising a nucleotide sequence encoding for said antibody.

In certain embodiments of said method, the cell strain is produced as described herein above and may comprise bacterial cells, such as gram-negative bacteria, e.g. E. coli, Proteus mirabilis, or Pseudomonas putidas, gram-positive bacteria, e.g. Bacillus brevis, Bacillus subtilis, Bacillus megaterium, Lactobacilli such as Lactobacillus zeae/casei or Lactobacillus paracasei, or Streptomyces, such as Streptomyces lividans,- eucariotic cells such as yeast, e.g. Pichia pastoris, Saccharomyces cerevisiae, Hansenula polymorpha, Schizosaccharomyces pombe, Schwanniomyces occidentalis, Kluyveromyces lactis, or Yarrowia lipolytica,' fugi, such as filamentous fungi, e.g. of the genus Trichoderma of Aspergillus, such as A. niger (e.g. subgenus A. awamori) and Aspergillus oryzae, Trichoderma reesei, Chrysosporium, such as C. lucknowense; protozoae, such as Leishmania, e.g. L. tarentolae'. insect cells, such as insect cells transfected a Baculovirus, e.g. AcNPV, such as insect cell lines from Spodoptera frugiperda, e.g. Sf-9 or Sf-21, Drosophila melanogaster, e.g. DS2, or Trichopulsia ni, e.g. High Five cells (BTI-TN- 5B1-4); mammalian cells such as hamster, e.g. Chinese hamster ovary such as K1-, DukX Bl 1-, DG44, Lecl3, or BHK, mouse, e.g. mouse myeloma such as NSO, Homo sapiens, e.g. Per.C6, AGE1.HN, HEK293.

In certain embodiments of said method, the cells may be hybridoma cells, e.g. as described herein.

In certain embodiments of said method, culturing may take place in a static suspension culture, an agitated suspension culture, a membrane-based culture, a matrix-based culture or a high cell density bioreactor; a vessel for such culturing may be selected from the group comprising a T-flask, a roller culture, a spinner culture, a stirred tank bioreactor, an airlift bioreactor, a static membrane-based or matrix-based culture system, a suspension bioreactor, a fluidized bed bioreactor, a ceramic bioreactor, a perfusion system, a hollow fiber bioreactor.

In certain embodiments of said method, the cells may be immobilized on a matrix.

A high cell density bioreactor is in particular a culture system capable of generating cell densities greater than 10⁸ cells/ml.

In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by a method comprising:

- generating a transgenic plant or animal comprising a nucleotide sequence encoding for the antibody;

- isolating the antibody from said plant or animal or a secretion or product of said plant or animal.

In a certain further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by isolating the antibody from a transgenic plant or transgenic animal or a secretion or product of a transgenic plant or transgenic animal having a nucleotide sequence encoding for the antibody. Said animal may e.g., be selected from a chicken, a mouse, a rat, a rabbit, a cow, a goat, a sheep, a pig; said secretion or product may e.g. be milk or an egg. Said plant may e.g. be selected from tobacco (N. tabacum orN. benthamiana), duckweed (Lemna minor), Chlamydomonas reinhardtii, rice, Arabidopsis thaliana, alfalfa (Medicago sativa), lettuce, maize.

The antibodies can in certain embodiments be isolated by physicochemical fractionation, e.g. size exclusion chromatography, precipitation, e.g. using ammonium sulphate, ion exchange chromatography, immobilized metal chelate chromatography gel filtration, zone electrophoresis; based on their classification e.g. binding to bacterial proteins A, G, or L, jacalin; antigen-specific affinity purification via immobilized ligands/antigens; if necessary, low molecular weight components can be removed by methods like dialysis, desalting, and diafiltration.

In some embodiments the antibody is encoded by a nucleotide sequence where the nucleotide sequence is a reverse transcription of an amino acid sequence from an antibody produced by one of the processes described herein.

Thus, the anti-DPP3 antibody may have the formats known in the art. Examples are human antibodies, monoclonal antibodies, humanized antibodies, chimeric antibodies, CDR-grafted antibodies. In a preferred embodiment antibodies according to the present invention are recombinantly produced antibodies as e.g. IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F-variable domain of heavy and/or light chain as e.g. chemically coupled antibodies (fragment antigen binding) including but not limited to Fab-fragments including Fab minibodies, single chain Fab antibody, monovalent Fab antibody with epitope tags, e.g. Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the CH3 domain; bivalent Fab or multivalent Fab, e.g. formed via multimerization with the aid of a heterologous domain, e.g. via dimerization of dHLX domains, e.g. Fab-dHLX-FSx2; F^b^- fragments, scFv-fragments, multimerized multivalent or/and multi-specific scFv-fragments, bivalent and/or bispecific diabodies, BITE® (bispecific T-cell engager), trifunctional antibodies, polyvalent antibodies, e.g. from a different class than G; single-domain antibodies, e.g. nanobodies derived from camelid or fish immunoglobulins and numerous others.

In a preferred embodiment the anti-DPP3 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 scFab fragment, Fab fragment, scFv fragment and bioavailability optimized conjugates thereof, such as PEGylated fragments. One of the most preferred formats is the scFab format.

Non-Ig scaffolds may be protein scaffolds and may be used as antibody mimics as they are capable to bind to ligands or antigens. In one embodiment non-Ig scaffolds may be selected from the group comprising tetranectin-based non-Ig scaffolds (e.g. described in US 2010/0028995), fibronectin scaffolds e.g. described vo. EP 1 266025,' lipocalin-based scaffolds e.g. described in WO 2011/154420),' ubiquitin scaffolds e.g. described in WO 2011/073214), transferrin scaffolds e.g. described in US 2004/0023334). protein A scaffolds (e.g. described in EP 2 231 860). ankyrin repeat based scaffolds (e.g. described in WO 2010/060748). microproteins preferably microproteins forming a cysteine knot) scaffolds e.g. described in EP 2314308). Fyn SH3 domain based scaffolds (e.g. described in WO 2011/023685) EGFR-A-domain based scaffolds (e.g. described in WO 2005/040229) and Kunitz domain based scaffolds (e.g. described in EP 1 941 867).

In one embodiment of the invention anti-DPP3 antibodies may be produced as outlined in Example 4 by synthesizing fragments of DPP3 as antigens or full-length DPP3. Thereafter, binder to said fragments are identified using the below described methods or other methods as known in the art.

Humanization of murine antibodies may be conducted according to the following procedure:

For humanization of an antibody of murine origin the antibody sequence is analysed for the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen. Based on structural modelling an appropriate FR of human origin is selected and the murine CDR sequences are transplanted into the human FR. Variations in the amino acid sequence of the CDRs or FRs may be introduced to regain structural interactions, which were abolished by the species switch for the FR sequences. This recovery of structural interactions may be achieved by random approach using phage display libraries or via directed approach guided by molecular modelling (Almagro & Fransson, 2008).

In another preferred embodiment, the anti-DPP3 antibody, anti-DPP3 antibody fragment, or anti-DPP3 non-Ig scaffold is a full-length antibody, antibody fragment, or non-Ig scaffold.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, the complementarity determining regions (CDR's) in the heavy chain comprises the sequences: SEQ ID NO: 76, SEQ ID NO: 77 and/or SEQ ID NO: 78 and the complementarity determining regions (CDR's) in the light chain comprises the sequences: SEQ ID NO: 79, KVS and/or SEQ ID NO: 80.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said monoclonal antibody or antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, the heavy chain comprises the sequence: SEQ ID NO: 81 and wherein the light chain comprises the sequence: SEQ ID NO: 82, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, the heavy chain comprises the sequence: SEQ ID NO: 208 and wherein the light chain comprises the sequence: SEQ ID NO: 209, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 or 5 amino acids in length comprised in SEQ ID NO: 70. In one embodiment said binder is an anti-DPP3 antibody or anti- DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 amino acids in length comprised in SEQ ID NO: 70. In another embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 5 amino acids in length comprised in SEQ ID NO: 70.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 or 5 amino acids in length comprised in SEQ ID NO: 71, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70.

In one embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 amino acids in length comprised in SEQ ID NO: 71, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70. In another embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 5 amino acids in length comprised in SEQ ID NO: 71, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 or 5 amino acids in length comprised in SEQ ID NO: 72, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70. In one embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 amino acids in length comprised in SEQ ID NO: 72, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70. In another embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 5 amino acids in length comprised in SEQ ID NO: 72, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 or 5 amino acids in length comprised in SEQ ID NO: 73, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70. In one embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4 amino acids in length comprised in SEQ ID NO: 72, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70. In another embodiment said binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 5 amino acids in length comprised in SEQ ID NO: 72, and wherein the epitope is comprised in DPP3 as depicted in SEQ ID NO: 70.

An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies. For example, the epitope is the specific piece of the antigen to which an antibody binds. The part of an antibody that binds to the epitope is called a paratope. The epitopes of protein antigens are divided into two categories, conformational epitopes and linear epitopes, based on their structure and interaction with the paratope. Conformational and linear epitopes interact with the paratope based on the 3-D conformation adopted by the epitope, which is determined by the surface features of the involved epitope residues and the shape or tertiary structure of other segments of the antigen.

A conformational epitope is formed by the 3-D conformation adopted by the interaction of discontinuous amino acid residues. A linear or a sequential epitope is an epitope that is recognized by antibodies by its linear sequence of amino acids, or primary structure and is formed by the 3-D conformation adopted by the interaction of contiguous amino acid residues.

In a specific embodiment of the invention the antibody is a monoclonal antibody or a fragment thereof.

In one embodiment of the invention the anti-DPP3 antibody or the anti-DPP3 antibody fragment is a human or humanized antibody or derived therefrom. In one specific embodiment one or more (murine) CDR’s are grafted into a human antibody or antibody fragment.

In certain embodiments of the invention relating to a human or humanized CDR-grafted antibody or antibody fragment thereof that binds to DPP3, the human or humanized CDR-grafted antibody or antibody fragment thereof comprises an antibody heavy chain (H chain) comprising: GFSLSTSGMS (SEQ ID NO: 76),

IWWNDNK (SEQ ID NO: 77),

ARNYSYDY (SEQ ID NO: 78) and/or further comprises an antibody light chain (L chain) comprising:

RSLVHSIGSTY (SEQ ID NO: 79),

KVS (not part of the sequencing listing),

SQSTHVPWT (SEQ ID NO: 80).

In one specific embodiment of the invention subject matter of the present invention is a human or humanized monoclonal antibody that binds to DPP3 or an antibody fragment thereof that binds to DPP3 wherein the heavy chain comprises at least one CDR selected from the group comprising:

GFSLSTSGMS (SEQ ID NO: 76),

IWWNDNK (SEQ ID NO: 77),

ARNYSYDY (SEQ ID NO: 78) and wherein the light chain comprises at least one CDR selected from the group comprising:

RSLVHSIGSTY (SEQ ID NO: 79),

KVS (not part of the sequencing listing),

SQSTHVPWT (SEQ ID NO: 80).

The anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold according to the present invention in particular embodiments exhibits an affinity towards human DPP3 in such that affinity constant is greater than 10'⁷ M, preferred 10'⁸ M, preferred affinity is greater than 10'⁹ M, most preferred higher than IO ¹⁰ M. A person skilled in the art knows that it may be considered to compensate lower affinity by applying a higher dose of compounds and this measure would not lead out-of-the- scope of the invention. The affinity constants may be determined according to the method as described in Example 5.

In certain embodiments of the invention relating to a monoclonal antibody or fragment that binds to DPP3 or an antibody fragment for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said antibody or fragment comprises the following sequence as a variable heavy chain:

SEQ ID NO: 74

QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMSVGWIRQPSGKGLEWLAHIWWNDNKSYNP ALKSRLTISRDTSNNQVFLKIASWTADTGTYFCARNYSYDYWGQGTTLTVSS and comprises the following sequence as a variable light chain:

SEQ ID NO: 75

DVWTQTPLSLSVSLGDPASISCRSSRSLVHSIGSTYLHWYLQKPGQSPKLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK.

In certain embodiments of the invention relating to a human or humanized monoclonal antibody or fragment that binds to DPP3 or an antibody fragment thereof for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said antibody or fragment comprises the following sequence as a heavy chain:

SEQ ID NO: 81

MDPKGSLSWRILLFLSLAFELSYGQITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQ PPGKALEWLAHIWWNDNKSYNPALKSRLTITRDTSKNQWLTMTNMDPVDTGTYYCARNY SYDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG and comprises the following sequence as a light chain:

SEQ ID NO: 82

METDTLLLWVLLLWVPGSTGDIVMTQTPLSLSVTPGQPASISCKSSRSLVHSIGSTYLYWYLQ KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

In a specific embodiment of the invention the antibody comprises the following sequence as a heavy chain: SEQ ID NO: 81 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99% and comprises the following sequence as a light chain: SEQ ID NO: 82 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

In certain embodiments of the invention relating to a human or humanized monoclonal antibody or fragment that binds to DPP3 or an antibody fragment thereof for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said antibody or fragment comprises the following sequence as a heavy chain:

SEQ ID NO: 208

QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALEWLAHIWWNDNKSYNP ALKSRLTITRDTSKNQWLTMTNMDPVDTGTYYCARNYSYDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTV PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPG and comprises the following sequence as a light chain:

SEQ ID NO: 209

DIVMTQTPLSLSVTPGQPASISCKSSRSLVHSIGSTYLYWYLQKPGQSPQLLIYKVSNRFSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

In a specific embodiment of the invention the antibody comprises the following sequence as a heavy chain: SEQ ID NO: 208 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99% and comprises the following sequence as a light chain: SEQ ID NO: 209 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

In a further aspect, procizumab (“PCZ”) is a monoclonal antibody obtainable by methods known in the art, or methods described herein. PCZ comprises two heavy chain sequences comprising SEQ ID NO: 208 and two light chain sequence comprising SEQ ID NO: 209. The respective SEQ ID NO: 81 for the heavy chain and SEQ ID NO: 82 for the light chain contain their respective N-terminal signal peptide sequences that can be used to manufacture the PCZ. The signal peptide sequence for the heavy chain is SEQ ID NO: 210 (MDPKGSLSWRILLFLSLAFELSYG) and for the light chain is SEQ ID NO: 211 (METDTLLLWVLLLWVPGSTG). As the PCZ is produced by the cell, the signal peptide sequence is cleaved off by cell before the protein is secreted. Culturing cells that express PCZ may be used to manufacture the protein at various scales. PCZ may be generated, for example, by any of the methods disclosed above used in the development and identification of the antibody. The DNA encoding the generated PCZ may be isolated and identified, for example, by DNA sequencing of the gene encoding the antibody against DPP3. Recombinant DNA technology well-known in the art may be used to manipulate the DNA. For example, the DNA encoding PCZ may be modified to make PCZ fragments and/or full-length PCZ to be combined with, for example, expression plasmid DNA. Further, the DNA can be codon optimized. The expression plasmid DNA encoding the PCZ or a fragment thereof may then be introduced, for example, by transfecting into cells used for culturing and expressing the PCZ or a fragment thereof. The culturing cells expressing the PCZ or a fragment thereof may be used to manufacture the PCZ or a fragment thereof at various scales. The culturing cells may be, for example, Chinese Hamster Ovary (CHO) cells (including strains K1-, DukX B11-, DG44, Lee 13), Human Embryonic Kidney 293 (HEK293) cells, baby hamster kidney (BHK21) cells, murine myeloma cells (NS0 and Sp2/0), Vero cells, MRC-5 cells, PerC.6 cells, AGE1.HN, or any other cells known in the art that are used to culture therapeutic proteins for manufacturing at various scales. Other non-mammalian cell lines or other cells may be used for culturing PCZ or a fragment thereof, such as, S. cerevisiae and E. coli and the others described above. The post translational modification of the protein should be taken into account for the choice of the cells for culturing.

In further particular embodiments of the present invention, the antibody or fragment that binds to DPP3 comprises a heavy chain fragment comprising SEQ ID NO: 212 and a light chain sequence as described herein in other embodiments, more particularly a light chain sequence according to SEQ ID NO: 209.

To assess the identity between two amino acid sequences, a pairwise alignment is performed. Identity defines the percentage of amino acids with a direct match in the alignment. In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, said level of DPP3 is the DPP3 concentration and/or an enzymatic DPP3 activity.

In one embodiment said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL.

In a specific embodiment of the invention said threshold of DPP3 concentration is 120 ng/ml or less, more preferred 100 ng/mL or less, even more preferred 80 ng/mL or less, even more preferred 60 ng/ml or less, even more preferred 50 ng/ml or less, most preferred said threshold is 40 ng/mL.

In one embodiment said threshold of enzymatic DPP3 activity is between 50 and 250 U/L, more preferred between 65 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L.

In a specific embodiment of the invention said threshold of enzymatic DPP3 activity is 250 U/L or less, more preferred 225 U/L or less, even more preferred between 200 U/L or less, most preferred said threshold is 185 U/L.

In a specific embodiment of the invention said bodily fluid is selected from the group comprising whole blood, serum or plasma.

In certain embodiments of the invention relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, said patient is

(i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery,

(iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving an anti-cancer therapy.

In one embodiment said patient is at risk of side effects if treated with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold.

In a preferred embodiment, the treatment with a DPP3 binder is initiated or changed immediately upon provision of the result of the sample analysis indicating the level of DPP3 in the sample. In further embodiments, the treatment may be initiated within 12 hours, preferably 6, 4, 2, 1, 0.5, 0.25 hours or immediately after receiving the result of the sample analysis.

In some embodiments, the method comprises or consists of a single and/ or multiple measurement of DPP3 in a sample from a patient in a single sample and/or multiple samples obtained at essentially the same time point, in order to guide and/ or monitor and/ or stratify a therapy, wherein said therapy is the administration of a DPP3 binder.

In one embodiment of the invention said anti- ADM antibody or anti-ADM fragment or anti- ADM non- Ig scaffold binds to the N-terminal part (amino acid 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). In a specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM.

In one embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment is a monoclonal antibody or monoclinal antibody fragment, wherein the heavy chain comprises the sequences:

CDR1: SEQ ID NO: 55 GYTFSRYW

CDR2: SEQ ID NO: 56 ILPGSGST

CDR3: SEQ ID NO: 57 TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1: SEQ ID NO: 58 QSIVYSNGNTY

CDR2: RVS

CDR3: SEQ ID NO: 59 FQGSHIPYT.

In a specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C), SEQ ID NO: 61 (AM-VH1), SEQ ID NO: 62 (AM-VH2-E40), SEQ ID NO: 63 (AM-VH3-T26-E55), SEQ ID NO: 64 (AM-VH4-T26-E40-E55) or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99% and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C), SEQ ID NO: 66 (AM-VL1), SEQ ID NO: 67 (AM-VL2-E40) or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%.

In a very specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment contains the following sequence as a heavy chain:

SEQ ID NO: 68 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, and comprises the following sequence as a light chain:

SEQ ID NO: 69 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments.

Subject matter of the present invention is a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, said formulation comprising a DPP3 binder.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold the pharmaceutical formulation comprises an anti-DPP3 antibody or anti-DPP3 -antibody fragment or anti-DPP3 scaffold according to the present invention.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is a solution, preferably a ready-to-use solution.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is in a freeze-dried state.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is administered intra-muscular.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is administered intra-vascular.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is administered via infusion. In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a critically ill patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, said pharmaceutical formulation is to be administered systemically.

In embodiments relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated with an Anti-ADM antibody, “patient that is to be treated” means in particular that the patient has been scheduled for administration of at least one dose of said Anti-ADM antibody within the next hour, the next two hours, three hours, or four hours; this also means in particular that said DPP3 binder is administered to said patient before said Anti-ADM antibody is to be administered to said patient.

In embodiments relating to a DPP3 binder for use in the treatment of a patient in need thereof that was pre-treated with an Anti-ADM antibody, “patient that was pre-treated with an Anti-ADM antibody” means in particular that the patient has been administered at least one dose of said Anti-ADM antibody, and subsequently, particularly within one hour, two hours, three hours, or four hours, or within a time frame of 1-2 hours, 1-3 hours, or 1-4 hours upon administration of said at least one dose of said Anti- ADM antibody, said DPP3 binder is administered to said patient.

In particular embodiments, the level of DPP3 is above a threshold in a sample of bodily fluid of said patient, particularly within one hour, two hours, three hours, or four hours, or within a time frame of 1- 2 hours, 1-3 hours, or 1-4 hours, upon administration of said Anti-ADM antibody, and said DPP3 binder is then administered to said patient. In other words, said DPP3 binder is administered to said patient when the level of DPP3 is above a threshold in a sample of bodily fluid of said patient after administration of said Anti-ADM antibody. More particularly, said level of DPP3 is below said threshold in a sample of bodily fluid of said patient before administration of said Anti-ADM antibody, and increases above said threshold in a sample of bodily fluid of said patient after administration of said Anti-ADM antibody.

In the embodiments relating to a DPP3 binder for use in the treatment of a patient in need thereof that is to be treated with an Anti-ADM antibody or that was pre-treated with an Anti-ADM antibody, the level of DPP3 is in particular as defined herein in the context of other embodiments; the threshold is in particular as defined herein in the context of other embodiments; the sample of bodily fluid is in particular as defined herein in the context of other embodiments; the level of DPP3 is in particular determined as defined herein in the context of other embodiments.

Subject matter of the present invention is an anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. In one embodiment said threshold of the DPP3 concentration (mass per volume) is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL.

In a specific embodiment of the invention said threshold of DPP3 concentration (mass per volume) is 120 ng/ml or less, more preferred 100 ng/mL or less, even more preferred 80 ng/mL or less, even more preferred 60 ng/ml or less, even more preferred 50 ng/ml or less, most preferred said threshold is 40 ng/mL.

In one embodiment said threshold of enzymatic DPP3 activity is between 50 and 250 U/L, more preferred between 65 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L.

In a specific embodiment of the invention said threshold of enzymatic DPP3 activity is 250 U/L or less, more preferred 225 U/L or less, even more preferred between 200 U/L or less, most preferred said threshold is 185 U/L.

In a specific embodiment of the invention said bodily fluid is selected from the group comprising whole blood, serum or plasma.

In certain embodiments of the invention relating to an anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving an anti-cancer therapy.

In one embodiment of the invention said anti- ADM antibody or anti-ADM fragment or anti- ADM non- Ig scaffold binds to the N-terminal part (amino acid 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). In a specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM.

In one embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment is a monoclonal antibody or monoclinal antibody fragment, wherein the heavy chain comprises the sequences:

CDR1: SEQ ID NO: 55 GYTFSRYW

CDR2: SEQ ID NO: 56 ILPGSGST

CDR3: SEQ ID NO: 57 TEGYEYDGFDY and wherein the light chain comprises the sequences: CDR1: SEQ ID NO: 58 QSIVYSNGNTY

CDR2: RVS

CDR3: SEQ ID NO: 59 FQGSHIPYT.

In a specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C), SEQ ID NO: 61 (AM-VH1), SEQ ID NO: 62 (AM-VH2-E40), SEQ ID NO: 63 (AM-VH3-T26-E55), SEQ ID NO: 64 (AM-VH4-T26-E40-E55) or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99% and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C), SEQ ID NO: 66 (AM-VL1), SEQ ID NO: 67 (AM-VL2-E40) or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%.

In a very specific embodiment of the invention said anti-ADM antibody or anti-ADM antibody fragment contains the following sequence as a heavy chain:

SEQ ID NO: 68 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, and comprises the following sequence as a light chain:

SEQ ID NO: 69 or a sequence that is > 95% identical to it, preferably > 98%, preferably > 99%, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments.

In further embodiments of the invention, the anti-ADM antibodies are the anti-ADM antibodies disclosed in WO2024017331A1, which is incorporated herein by reference.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156) : NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 158): RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159): KVSNRFS and/or

CDR3 (SEQ ID No: 160): FQGSHFPYT or a sequence wherein one or two amino acids are exchanged from the original CDR sequences in at least one of the CDR sequences provided that the binding affinity to ADM is diminished by not more than 20%.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain variable region sequence shown in any one of SEQ ID NO: 161 and 163 , and the monoclonal antibody The cloned antibody comprises the light chain variable region sequence shown in any one of SEQ ID NO: 162, 164 and 165, wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 161 and the light chain variable region sequence shown in SEQ ID NO: 162, the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 164, or the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 165.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 167 and the light chain shown in SEQ ID NO: 166.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 169 and the light chain shown in SEQ ID NO: 168.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 171 and the light chain shown in SEQ ID NO: 170.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 173 and the light chain shown in SEQ ID NO: 172. In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequence:

(i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and

(b) the light chain variable region of the monoclonal antibody or antibody fragment comprises the following CDR sequence:

(i) RAX? Xg GIX9 X10 YLA, where X7 is selected from amino acids S or A, Xg is selected from amino acids Q or E, X9 is selected from amino acids S or G, X10 is selected from amino acids S or E,

(ii) DXn SX12 X13 X14 X15, where Xu is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, X13 is selected from amino acids L or V, X14 is selected from amino acids E or D, X15 is selected from amino acids T or A,

(iii) QQYDX16 LX17 LXig, where Xi6 is selected from amino acids N or D, X17 is selected from amino acids P or D, Xi is selected from amino acids T or S.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises HCDR1, HCDR2 and HCDR3 sequences, wherein the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 174, 182 and 186, and the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 175, 180, 185 and 189, and the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 176 and 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises LCDR1, LCDR2 and LCDR3 sequences, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 177, 183 and 184, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 178, 187, 188 and 190 , and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 179 , 191 and 192.

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein (a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYNGN (as shown in SEQ ID NO: 175),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 or 194 , and the light chain variable region sequence as shown in SEQ ID NO: 200 , wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 and the light chain variable region sequence as shown in SEQ ID NO: 200 , or wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 194 and the light chain variable region sequence as shown in SEQ ID NO: 200. In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182), (ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RAAEGIGSYLA (as shown in SEQ ID NO: 184),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYSGN (as shown in SEQ ID NO: 185),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i)RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187), (iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNVDT (as shown in SEQ ID NO: 188),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174), (ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DTSDLDT (as shown in SEQ ID NO: 190),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178), (iii) QQYDDLDLT (as shown in SEQ ID NO: 191).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLPLS (shown in SEQ ID NO: 192).

In even more particular embodiments of the present invention, said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 to 199, the light chain variable region sequence shown in any one of SEQ ID NO: 200 to 207, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 and the light chain variable region sequence as shown in SEQ ID NO: 200, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 202, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 197 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 204, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 205, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 206, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 207.

Subject matter of the present invention is a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, comprising an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non-Ig scaffold.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is a solution, preferably a ready-to-use solution.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is in a freeze-dried state.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is administered intra-muscular. In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is administered intra-vascular.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is administered via infusion.

In certain embodiments of the invention relating to a pharmaceutical formulation for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to the present invention, said pharmaceutical formulation is to be administered systemically.

Pre-Treatment Procizumab

In embodiments relating to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold for use in the treatment of a patient in need thereof that is to be treated with a DPP3 binder, “patient that is to be treated” means in particular that the patient has been scheduled for administration at least one dose of said DPP3 binder within the next hour, the next two hours, three hours, four hours, this also means in particular that said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold is administered to said patient after said DPP3 binder is to be administered to said patient.

In embodiments relating to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold for use in the treatment of a patient in need thereof that was pre-treated with a DPP3 binder, “patient that was pre-treated with a DPP3 binder” means in particular that the patient has been administered at least one dose of said DPP3 binder, and subsequently, particularly within one hour, two hours, three hours, four hours , or within a time frame of 1-2 hours, 1-3 hours, 1-4 hours, upon administration of said at least one dose of said DPP3 binder, said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold is administered to said patient.

In particular embodiments, the level of DPP3 is above a threshold in a sample of bodily fluid of said patient, particularly within one hour, two hours, three hours, four hours, or within a time frame of 1-2 hours, 1-3 hours, 1-4 hours upon administration of a DPP3 binder, and said anti-ADM antibody or anti- ADM antibody fragment or anti-ADM scaffold is then administered to said patient. In other words, said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold is administered to said patient when the level of DPP3 is above a threshold in a sample of bodily fluid of said patient after administration of said DPP3 binder. More particularly, said level of DPP3 is above said threshold in a sample of bodily fluid of said patient before administration of said DPP3 binder, and decreases below said threshold in a sample of bodily fluid of said patient after administration of said DPP3 binder.

In the embodiments relating to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM scaffold for use in the treatment of a patient in need thereof that is to be treated with a DPP3 binder or that was pre-treated with a DPP3 binder, the level of DPP3 is in particular as defined herein in the context of other embodiments; the threshold is in particular as defined herein in the context of other embodiments; the sample of bodily fluid is in particular as defined herein in the context of other embodiments; the level of DPP3 is in particular determined as defined herein in the context of other embodiments.

In certain embodiments of the invention, a level of DPP3 in a sample of a bodily fluid of a patient is above a threshold and the patient is identified as having a level of DPP3 above a threshold, in particular in said sample of bodily fluid.

Thus, certain embodiments of the invention relate to Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof, wherein said patient is identified as having a level of DPP3 above a threshold, in particular in said sample of bodily fluid. In one embodiment said fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group,

Thus, certain further embodiments of the invention relate to an anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. In one embodiment said DPP3 binder is Adrenomedullin Gly or fragments or derivates or modifications thereof as defined herein.

In certain embodiments of the invention, a level of DPP3 in a sample of a bodily fluid of a patient is above a threshold and the treatment according to the invention comprises determining the level of DPP3 in a sample bodily fluid of said patient, and administering the treatment according to the invention if said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. Methods of determining level of DPP3 are disclosed herein.

Thus, certain embodiments of the invention relate to Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said Adrenomedullin- Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof is administered if said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. In one embodiment said fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group.

Thus, certain further embodiments of the invention relate to an anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said anti- ADM antibody is administered if said patient is identified as having a level of DPP3 above a threshold, in particular in said sample of bodily fluid. Methods of determining level of DPP3 are disclosed herein. In one embodiment said DPP3 binder is Adrenomedullin Gly or fragments or derivates or modifications thereof as defined herein.

In certain embodiments of the invention, the compound(s) as defined herein for the use in a treatment as defined herein relates to a) a method of treatment comprising administering said compound to the patient in need thereof in said treatment, or b) to the use of said compound(s) for the production of a medicament or pharmaceutical composition for use in the said treatment, or c) for a pharmaceutical composition comprising said compound and confectioned for the use in said treatment, or d) to the use of said compound in said treatment.

General Definitions

Throughout the specification the term “ADM-Gly” includes all splice variants of ADM-Gly if not stated otherwise. Throughout the specification the term “mature ADM” includes all splice variants of mature ADM if not stated otherwise.

As used herein, „amino acids“ are particularly naturally occurring amino acids, more particularly the canonical 20 amino acids.

As used herein, the terms "comprising" and "including" or grammatical variants thereof are to be taken as specifying at least the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. This term encompasses the terms "consisting of’ and "consisting essentially of’ that are understood to specify only the stated feature, integers, steps or components to the exclusion of any additional features.

As used herein “concentration” particularly refers to mass per volume, e.g. mass of DPP3 in a volume of sample.

The term "consisting of’ means that no further component (or likewise features, integers, steps and the like) is present.

The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, biological and biophysical arts.

The term "pharmaceutical composition" means a pharmaceutical ingredient in combination with at least one pharmaceutically acceptable excipient, which is in such form as to permit the biological activity of a pharmaceutical ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. The term "pharmaceutical ingredient" means a therapeutic composition which can be optionally combined with pharmaceutically acceptable excipients to provide a pharmaceutical composition or dosage form.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (see (Singer et al., 2016)). Organ dysfunction can be identified as an acute change in total SOFA score >2 points consequent to the infection. The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction. A SOFA score >2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention, if not already being instituted.

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA, i.e., alteration in mental status, systolic blood pressure <100 mm Hg, or respiratory rate >22/min.

Shock is characterized by decreased oxygen delivery and/or increased oxygen consumption or inadequate oxygen utilization leading to cellular and tissue hypoxia. It is a life-threatening condition of circulatory failure and most commonly manifested as hypotension (systolic blood pressure less than 90 mm Hg or MAP less than 65 mmHg). Shock is divided into four main types based on the underlying cause: hypovolemic, cardiogenic, obstructive, and distributive shock (Vincent & De Backer, 2013).

Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40% (Singer et al., 2016). The primary infection is most commonly caused by bacteria, but also may be by fungi, viruses or parasites. It may be located in any part of the body, but most commonly in the lungs, brain, urinary tract, skin or abdominal organs. It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death. Frequently, people with septic shock are cared for in intensive care units. It most commonly affects children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with infection as effectively as those of healthy adults. The mortality rate from septic shock is approximately 25-50%.

Cardiogenic shock (CS) is defined as a state of critical end-organ hypoperfusion due to reduced cardiac output. Notably, CS forms a spectrum that ranges from mild hypoperfusion to profound shock. Established criteria for the diagnosis of CS are: (i) systolic blood pressure, <90 mmHg for >30 min or vasopressors required to achieve a blood pressure >90 mmHg; (ii) pulmonary congestion or elevated left-ventricular filling pressures; (iii) signs of impaired organ perfusion with at least one of the following criteria: (a) altered mental status; (b) cold, clammy skin; (c) oliguria (< 0.5 mL/kg/h or <30 mL/h); (d) increased serum-lactate (Reynolds & Hochman, 2008). 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 (4%) or free wall rupture (2%), and acute severe mitral regurgitation (7%) are less frequent causes of CS after AMI (Hochman et al., 2000).

Non-AMI-related CS may be caused by decompensated valvular heart disease, acute myocarditis, arrhythmias, etc. with heterogeneous treatment options. This translates in 40 000 to 50 000 patients per year in the USA and 60 000 to 70 000 in Europe. Despite advances in treatment mainly by early revascularization with subsequent mortality reduction, CS remains the leading cause of death in AMI with mortality rates still approaching 40-50% according to recent registries and randomized trials (Goldberg et al., 2009).

Heart failure (HF) is a cardiac condition that occurs, when a problem with the structure or function of the heart impairs its ability to supply sufficient blood flow to meet the body's needs. It can cause a large variety of symptoms, particularly shortness of breath (SOB) at rest or during exercise, signs of fluid retention such as pulmonary congestion or ankle swelling and objective evidence of an abnormality of the structure or function of the heart at rest.

Heart failure is a clinical syndrome characterized by a constellation of symptoms and signs caused by cardiac dysfunction. It is one of the major causes of morbidity and mortality in the developed countries, with a prevalence of 1-2%. Heart failure can be grouped into chronic HF and acute HF. Patients with chronic HF can be grouped into stable chronic HF, worsening signs and symptoms of chronic HF and acute decompensation of chronic HF. Acute heart failure (AHF) is defined as a rapid onset of signs and symptoms of heart failure resulting in the need for urgent therapy or hospitalization. AHF can present as acute de novo HF (new onset of AHF in a patient without previous cardiac dysfunction) or acute decompensation of chronic HF.

Patients with chronic heart failure (HF) may include patients with worsening signs and symptoms of chronic heart failure and acute decompensation of chronic heart failure.

Chronic HF with worsening signs and symptoms is in particular characterized by:

(i) the presence of structural or functional failure of the heart that impairs its ability to supply sufficient blood flow to meet body's needs,

(ii) volume overload (manifested by pulmonary and/ or systemic congestion) and/ or profound depression of cardiac output (manifested by hypotension, renal insufficiency and/ or a shock syndrome) and whereas the patient is not in need of urgent therapy and does not require hospitalization, but is in need of therapy adjustment. Chronic heart failure may also decompensate (termed acute decompensated heart failure or acute decompensated chronic heart failure), which is most commonly the result from an intercurrent illness (such as pneumonia), myocardial infarction, arrhythmias, uncontrolled hypertension or a patient's failure to maintain fluid restriction, diet or medication.

New onset acute HF and acute decompensated chronic HF are characterized by:

(i) the presence of structural or functional failure of the heart that impairs its ability to supply sufficient blood flow to meet body's needs,

(ii) volume overload (manifested by pulmonary and/ or systemic congestion) and/ or profound depression of cardiac output (manifested by hypotension, renal insufficiency and/ or a shock syndrome) and whereas the patient is in need of urgent therapy or therapy adjustment and does require hospitalization.

The above definitions of acute heart failure that either new-onset AHF or acute decompensated HF or acute decompensated chronic HF or worsening signs/symptoms of chronic heart failure are in line with Voors et al., European Journal of Heart Failure (2016), 18, 716 - 726.

Numerous ways to treat cancer have been developed, and there are more to come in the future (Wolfgang Link, pages 7-76 in “Principles of Cancer Treatment and Anticancer Drug Development”, ISBN 978-3- 030-18721-7, published September 20, 2019; Alecsandru Ioan Baba and Cornel Catoi in “Comparative Oncology”; Bucharest (RO): The Publishing House of the Romanian Academy; 2007. ISBN-10: 973- 27-1457-3; https://www.cancer.gov/about-cancer/treatment/types). In the present application, all of these shall be comprised under “cancer therapies”. Ways of treating cancer depend on the type of cancer and on how advanced it is. Treatments might be given only once, or repeatedly, as a single type of treatment, or as a combination of different types of treatments. Cancer therapies include (https://www.cancer.gov/about-cancer/treatment/types): Chemotherapy, hormone therapy, hyperthermia, immunotherapy (including T-cell transfer therapy of the type tumor-infiltrating lymphocytes (or TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy), photodynamic therapy, radiation therapy, stem cell transplant, surgery, targeted therapy.

The following embodiments form also part of the present invention:

1. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpeptidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiment 1, wherein said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 or 2, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said Adrenomedullin- Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof is administered if said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 3, wherein said fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 4, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3 in said sample. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 5, wherein said threshold of DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 6, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 65 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 7, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 8, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock, or (vi) a patient with cancer optionally receiving an anti-cancer therapy. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 9, wherein said ADM- Gly is administered to said patient at a dosage of 1-1000 pg/kg, preferably 5-750 pg/kg, more preferably 10-500 pg/kg, more preferably 15-400 pg/kg, more preferably 20-250 pg/kg, most preferred 25-100 pg/kg. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 10, wherein said fragments of ADM-Gly (SEQ ID NO: 6) are selected from the group comprising SEQ ID NO: 7 to 53 and SEQ ID NO: 83 to 129. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a patient in need thereof according to embodiments 1 to 11, wherein said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof is modified a) by being covalently bound to another moiety, wherein said moiety is selected from one or more from the group comprising (i) an extension by one or more amino acids, (ii) a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin, and (iii) a natural or synthetic polymer, wherein said natural or synthetic polymer is selected from the group comprising HAP, ELP, a carbohydrate, a polysaccharide, PAS, PSA, GLK, XTEN and PEG, preferably ELP, more preferably a carbohydrate, more preferably a polysaccharide, more preferably PAS, more preferably PSA, more preferably GLK, more preferably XTEN and most preferably PEG, or b) via non-covalent binding to serum Albumin, or c) by amino acid manipulation via site directed mutagenesis, including the insertion, deletion or alteration of one or more amino acids within said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiment 13, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3. A DPP3 binder for use in the treatment of a patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 and 14, wherein said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 and 14, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 60 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 16, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 17, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving an anti-cancer therapy. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 18, wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal part (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiment 19, wherein said anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM, wherein the heavy chain comprises the sequences:

CDR1 (SEQ ID NO: 55): GYTFSRYW

CDR2 (SEQ ID NO: 56): ILPGSGST

CDR3 (SEQ ID NO: 57): TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1 (SEQ ID NO: 58): QSIVYSNGNTY

CDR2: RVS

CDR3 (SEQ ID NO: 59): FQGSHIPYT. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 21, wherein said anti- ADM antibody or anti- ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C)

QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTN YNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK or a sequence that is > 95% identical to it, and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDQATISCRSSQSrVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFS

GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI

FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRD

SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRD

SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment according to embodiments 13 to 22, wherein said anti-ADM antibody or anti-ADM antibody fragment comprises the following sequence as a heavy chain:

SEQ ID NO: 68

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTN YNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a sequence that is > 95% identical to it, and comprises the following sequence as a light chain:

SEQ ID NO: 69

DWLTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 23, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti- DPP3 non-Ig scaffolds. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 14 to 24 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70 (full-length DPP3). A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 25 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 26, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 24 to 27 wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 27 to 28, wherein said anti-DPP3 monoclonal antibody or monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 24 to 29, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 24 to 29, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 32, wherein said DPP3 binder is Adrenomedullin Gly or fragments or derivates or modifications thereof as defined herein. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 or 33, wherein said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 34, wherein, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said anti- ADM antibody is administered if said patient is identified as having a level of DPP3 above a threshold, in particular in said sample of bodily fluid. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 35, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 32 to 36, wherein said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder to embodiment 32 to 36, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 60 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 38, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 39, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving chemotherapeutic drugs. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 40, wherein said anti- ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal part (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 41, wherein said anti- ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said anti- ADM antibody or anti-ADM antibody fragment is a monoclonal antibody or fragment that binds to ADM, wherein the heavy chain comprises the sequences:

CDR1: (SEQ ID NO: 55) GYTFSRYW

CDR2: (SEQ ID NO: 56) ILPGSGST

CDR3: (SEQ ID NO: 57) TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1: (SEQ ID NO: 58) QSIVYSNGNTY

CDR2: RVS

CDR3: (SEQ ID NO: 59) FQGSHIPYT. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 43, wherein said anti- ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C)

QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTN YNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK or a sequence that is > 95% identical to it, and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDQATISCRSSQSrVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFS

GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI

FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS

STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRD

SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRD

SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV

FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 44, wherein said anti- ADM antibody comprises the following sequence as a heavy chain:

SEQ ID NO: 68 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTN YNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a sequence that is > 95% identical to it, and comprises the following sequence as a light chain: SEQ ID NO: 69 DWLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95% of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 45, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 34 to 46, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 47, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 48, wherein said anti- DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 49, wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 49 to 50, wherein said anti- DPP3 monoclonal antibody or anti-DPP3 monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 51, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 51, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain of said anti-ADM antibody or anti- ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156) : NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 158): RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159): KVSNRFS and/or

CDR3 (SEQ ID No: 160): FQGSHFPYT or a sequence wherein one or two amino acids are exchanged from the original CDR sequences in at least one of the CDR sequences provided that the binding affinity to ADM is diminished by not more than 20%. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain variable region sequence shown in any one of SEQ ID NO: 161 and 163, and wherein the monoclonal antibody comprises the light chain variable region sequence shown in any one of SEQ ID NO: 162, 164 and 165, wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 161 and the light chain variable region sequence shown in SEQ ID NO: 162, wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 164, or the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 165. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiment54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 167 and the light chain shown in SEQ ID NO: 166. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 169 and the light chain shown in SEQ ID NO: 168. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 171 and the light chain shown in SEQ ID NO: 170. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 173 and the light chain shown in SEQ ID NO: 172. 60. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti- ADM antibody or anti- ADM antibody fragment or anti- ADM non- Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequence:

(i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and

(b) the light chain variable region of the monoclonal antibody or antibody fragment comprises the following CDR sequence:

(i) RAX7 X8 GIX9 XI 0 YLA, where X7 is selected from amino acids S or A, X8 is selected from amino acids Q or E, X9 is selected from amino acids S or G, X10 is selected from amino acids S or E,

(ii) DX11 SX12 X13 X14 X15, where XI 1 is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, XI 3 is selected from amino acids L or V, XI 4 is selected from amino acids E or D, XI 5 is selected from amino acids T or A,

(iii) QQYDX16 LX17 LXis, where Xi6 is selected from amino acids N or D, X17 is selected from amino acids P or D, Xis is selected from amino acids T or S.

61. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises HCDR1, HCDR2 and HCDR3 sequences, wherein the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 174, 182 and 186, and the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 175, 180, 185 and 189, and the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 176 and 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises LCDR1, LCDR2 and LCDR3 sequences, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 177, 183 and 184, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 178, 187, 188 and 190 , and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 179 , 191 and 192.

62. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYNGN (as shown in SEQ ID NO: 175),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

63. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177,

(ii) DASNLET (as shown in SEQ ID NO: 178,

(iii) QQYDNLPLT (shown in SEQ ID NO: 179. 64. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 or 194 , and the light chain variable region sequence as shown in SEQ ID NO: 200 , wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 and the light chain variable region sequence as shown in SEQ ID NO: 200 , or wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 194 and the light chain variable region sequence as shown in SEQ ID NO: 200.

65. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174,

(ii) SAYQGN (as shown in SEQ ID NO: 180,

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177,

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

66. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182), (ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

67. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RAAEGIGSYLA (as shown in SEQ ID NO: 184),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

68. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYSGN (as shown in SEQ ID NO: 185),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and (b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

69. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

70. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

71. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNVDT (as shown in SEQ ID NO: 188),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

72. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187), (iii) QQYDNLPLT (shown in SEQ ID NO: 179).

73. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DTSDLDT (as shown in SEQ ID NO: 190),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

74. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLDLT (as shown in SEQ ID NO: 191). 75. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLPLS (shown in SEQ ID NO: 192).

76. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 to 199, the light chain variable region sequence shown in any one of SEQ ID NO: 200 to 207, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 and the light chain variable region sequence as shown in SEQ ID NO: 200, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 202, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 197 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 204, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 205, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 206, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 207.

77. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 76, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds.

78. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 77 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70 (full-length DPP3).

79. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 78 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71.

80. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 79, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment.

81. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 80 wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80.

82. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 81, wherein said anti-DPP3 monoclonal antibody or monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment.

83. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 82, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

84. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 82, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

85. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156) : NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 158) : RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159) : KVSNRFS and/or

CDR3 (SEQ ID No: 160) : FQGSHFPYT or a sequence wherein one or two amino acids are exchanged from the original CDR sequences in at least one of the CDR sequences provided that the binding affinity to ADM is diminished by not more than 20%.

86. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 85, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain variable region sequence shown in any one of SEQ ID NO: 161 and 163 , and the monoclonal antibody The cloned antibody comprises the light chain variable region sequence shown in any one of SEQ ID NO: 162 , 164 and 165 , wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 161 and the light chain variable region sequence shown in SEQ ID NO: 162, the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 164, or the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 165.

87. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 85, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 167 and the light chain shown in SEQ ID NO: 166.

88. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 85, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 169 and the light chain shown in SEQ ID NO: 168.

89. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 85, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 171 and the light chain shown in SEQ ID NO: 170.

90. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment85, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 173 and the light chain shown in SEQ ID NO: 171.

91. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequence: (i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and

(b) the light chain variable region of the monoclonal antibody or antibody fragment comprises the following CDR sequence:

(i) RAX? Xs GIX9 X10 YLA, where X7 is selected from amino acids S or A, Xs is selected from amino acids Q or E, X9 is selected from amino acids S or G, X10 is selected from amino acids S or E,

(ii) DXn SX12 X13 X14 X15, where Xu is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, X13 is selected from amino acids L or V, X14 is selected from amino acids E or D, X15 is selected from amino acids T or A,

(iii) QQYDX16 LX17 LXis, where Xi6 is selected from amino acids N or D, X17 is selected from amino acids P or D, Xis is selected from amino acids T or S.

92. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises HCDR1, HCDR2 and HCDR3 sequences, wherein the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 174, 182 and 186, and the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 175, 180, 185 and 189, and the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 176 and 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises LCDR1, LCDR2 and LCDR3 sequences, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 177, 183 and 184, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 178, 187, 188 and 190 , and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 179, 191 and 192.

93. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein (a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174,

(ii) SAYNGN (as shown in SEQ ID NO: 175,

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177,

(ii) DASNLET (as shown in SEQ ID NO: 178,

(iii) QQYDNLPLT (shown in SEQ ID NO: 179.

94. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

95. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 or 194, and the light chain variable region sequence as shown in SEQ ID NO: 200, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 and the light chain variable region sequence as shown in SEQ ID NO: 200 , or wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 194, and the light chain variable region sequence as shown in SEQ ID NO: 200.

96. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

97. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179). 98. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182,

(ii) SAYQGN (as shown in SEQ ID NO: 180,

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RAAEGIGSYLA (as shown in SEQ ID NO: 184,

(ii) DASNLET (as shown in SEQ ID NO: 178,

(iii) QQYDNLPLT (shown in SEQ ID NO: 179.

99. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYSGN (as shown in SEQ ID NO: 185),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i)RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

100. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein (a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

101. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

102. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNVDT (as shown in SEQ ID NO: 188),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

103. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

104. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and (b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DTSDLDT (as shown in SEQ ID NO: 190),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

105. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLDLT (as shown in SEQ ID NO: 191).

106. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLPLS (shown in SEQ ID NO: 192).

107. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 to 199, the light chain variable region sequence shown in any one of SEQ ID NO: 200 to 207, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 and the light chain variable region sequence as shown in SEQ ID NO: 200, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 202, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 197 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 204, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 205, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 206, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 207.

108. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 107, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds.

109. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 108, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70.

110. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 109, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71.

111. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 110, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment.

112. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 111, wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti- DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences: SEQ ID NO: 79, KVS and/or SEQ ID NO: 80. 113. An anti- ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 112, wherein said anti-DPP3 monoclonal antibody or anti-DPP3 monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment.

114. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 113, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

115. An anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 113, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

Furthermore, the following embodiments form also part of the present invention (aspect B):

1. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpeptidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiment 1 , wherein said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 or 2, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof is administered if said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 3, wherein said fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 4, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3 in said sample. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 5, wherein said threshold of DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 6, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 65 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 7, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 8, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock, or (vi) a patient with cancer optionally receiving an anti-cancer therapy. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 9, wherein said ADM-Gly is administered to said patient at a dosage of 1-1000 pg/kg, preferably 5-750 pg/kg, more preferably 10-500 pg/kg, more preferably 15-400 pg/kg, more preferably 20-250 pg/kg, most preferred 25-100 pg/kg. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 10, wherein said fragments of ADM-Gly (SEQ ID NO: 6) are selected from the group comprising SEQ ID NO: 7 to 53 and SEQ ID NO: 83 to 129. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to embodiments 1 to 11, wherein said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof is modified a) by being covalently bound to another moiety, wherein said moiety is selected from one or more from the group comprising (i) an extension by one or more amino acids, (ii) a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin, and (iii) a natural or synthetic polymer, wherein said natural or synthetic polymer is selected from the group comprising HAP, ELP, a carbohydrate, a polysaccharide, PAS, PSA, GLK, XTEN and PEG, preferably ELP, more preferably a carbohydrate, more preferably a polysaccharide, more preferably PAS, more preferably PSA, more preferably GLK, more preferably XTEN and most preferably PEG, or b) via non-covalent binding to serum Albumin, or c) by amino acid manipulation via site directed mutagenesis, including the insertion, deletion or alteration of one or more amino acids within said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 13, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3. A DPP3 binder for use in the treatment of a disease or medical condition in a patient that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 and 14, wherein said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 and 14, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 60 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 16, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 17, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving an anti-cancer therapy. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 18, wherein said anti- ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal part (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 19, wherein said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM, wherein the heavy chain comprises the sequences:

CDR1 (SEQ ID NO: 55): GYTFSRYW

CDR2 (SEQ ID NO: 56): ILPGSGST

CDR3 (SEQ ID NO: 57): TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1 (SEQ ID NO: 58): QSIVYSNGNTY

CDR2: RVS

CDR3 (SEQ ID NO: 59): FQGSHIPYT. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 21, wherein said anti- ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTN

YNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVS

SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGST

NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK or a sequence that is > 95% identical to it, and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDQATISCRSSQSrVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFS

GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1) DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment according to embodiments 13 to 22, wherein said anti-ADM antibody or anti-ADM antibody fragment comprises the following sequence as a heavy chain:

SEQ ID NO: 68

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTN YNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a sequence that is > 95% identical to it, and comprises the following sequence as a light chain:

SEQ ID NO: 69

DWLTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti- ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 23, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 14 to 24 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70 (full-length DPP3). A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 25 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 26, wherein said anti- DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 24 to 27 wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences: SEQ ID NO: 79, KVS and/or SEQ ID NO: 80. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 27 to 28, wherein said anti- DPP3 monoclonal antibody or monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 24 to 29, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 24 to 29, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 32, wherein said DPP3 binder is Adrenomedullin Gly or fragments or derivates or modifications thereof as defined herein. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 or 33, wherein said patient is identified as having level of DPP3 above a threshold, in particular in said sample of bodily fluid. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 34, wherein, wherein the level of DPP3 is determined in a sample bodily fluid of said patient, and wherein said anti-ADM antibody is administered if said patient is identified as having a level of DPP3 above a threshold, in particular in said sample of bodily fluid. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 35, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 32 to 36, wherein said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder to embodiment 32 to 36, wherein said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 60 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 38, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 39, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock or (vi) a patient with cancer optionally receiving chemotherapeutic drugs. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 40, wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non- Ig scaffold binds to the N-terminal part (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38). An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 41, wherein said anti-ADM antibody or anti-ADM antibody fragment or anti- ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said anti-ADM antibody or anti-ADM antibody fragment is a monoclonal antibody or fragment that binds to ADM, wherein the heavy chain comprises the sequences:

CDR1: (SEQ ID NO: 55) GYTFSRYW

CDR2: (SEQ ID NO: 56) ILPGSGST

CDR3: (SEQ ID NO: 57) TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1: (SEQ ID NO: 58) QSIVYSNGNTY

CDR2: RVS

CDR3: (SEQ ID NO: 59) FQGSHIPYT. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 43, wherein said anti-ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region: SEQ ID NO: 60 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTN YNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGST NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK or a sequence that is > 95% identical to it, and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DWMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTQSPLSLPVTLGQPASISCRSSQSrVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 44, wherein said anti-ADM antibody comprises the following sequence as a heavy chain: SEQ ID NO: 68 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTN YNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ

YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a sequence that is > 95% identical to it, and comprises the following sequence as a light chain: SEQ ID NO: 69 DWLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Ill or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95% of SEQ ID NO: 68 and SEQ ID NO: 69, respectively, more particularly such fragments are Fab fragments. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 45, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 34 to 46, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 47, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 48, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 49, wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences: SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 49 to 50, wherein said anti-DPP3 monoclonal antibody or anti-DPP3 monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 51, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 51, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence: SEQ ID NO: 209 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments. A DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non- Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain of said anti-ADM antibody or anti- ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156) : NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 158) : RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159) : KVSNRFS and/or

CDR3 (SEQ ID No: 160) : FQGSHFPYT or a sequence wherein one or two amino acids are exchanged from the original CDR sequences in at least one of the CDR sequences provided that the binding affinity to ADM is diminished by not more than 20%. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain variable region sequence shown in any one of SEQ ID NO: 161 and 163, and wherein the monoclonal antibody comprises the light chain variable region sequence shown in any one of SEQ ID NO: 162, 164 and 165, wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 161 and the light chain variable region sequence shown in SEQ ID NO: 162, wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 164, or the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 165. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 167 and the light chain shown in SEQ ID NO: 166. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 169 and the light chain shown in SEQ ID NO: 168. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 171 and the light chain shown in SEQ ID NO: 170. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 54, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 173 and the light chain shown in SEQ ID NO: 172. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 13 to 20, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequence:

(i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and

(b) the light chain variable region of the monoclonal antibody or antibody fragment comprises the following CDR sequence:

(i) RAX7 X8 GIX9 XI 0 YLA, where X7 is selected from amino acids S or A, X8 is selected from amino acids Q or E, X9 is selected from amino acids S or G, X10 is selected from amino acids S or E, (ii) DX11 SX12 X13 X14 X15, where XI 1 is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, XI 3 is selected from amino acids L or V, X14 is selected from amino acids E or D, XI 5 is selected from amino acids T or A,

(iii) QQYDX16 LX17 LXis, where Xi6 is selected from amino acids N or D, X17 is selected from amino acids P or D, Xis is selected from amino acids T or S.

61. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises HCDR1, HCDR2 and HCDR3 sequences, wherein the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 174, 182 and 186, and the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 175, 180, 185 and 189, and the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 176 and 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises LCDR1, LCDR2 and LCDR3 sequences, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 177, 183 and 184, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 178, 187, 188 and 190 , and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 179 , 191 and 192.

62. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYNGN (as shown in SEQ ID NO: 175),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178), (iii) QQYDNLPLT (shown in SEQ ID NO: 179).

63. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

64. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 or 194, and the light chain variable region sequence as shown in SEQ ID NO: 200, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 and the light chain variable region sequence as shown in SEQ ID NO: 200, or wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 194 and the light chain variable region sequence as shown in SEQ ID NO: 200.

65. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein (a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

66. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(a) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

67. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RAAEGIGSYLA (as shown in SEQ ID NO: 184),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

68. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYSGN (as shown in SEQ ID NO: 185),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i)RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

69. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180), (iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

70. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

71. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and (b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNVDT (as shown in SEQ ID NO: 188),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

72. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

73. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DTSDLDT (as shown in SEQ ID NO: 190),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

74. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLDLT (as shown in SEQ ID NO: 191).

75. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178), (iii) QQYDDLPLS (shown in SEQ ID NO: 192).

76. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiment 60, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 to 199, the light chain variable region sequence shown in any one of SEQ ID NO: 200 to 207, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 and the light chain variable region sequence as shown in SEQ ID NO: 200, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 202, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 197 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 204, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 205, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 206, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 207.

77. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 76, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds.

78. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 77 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70 (full- length DPP3).

79. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 78 wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71.

80. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 79, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment.

81. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 80 wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences: SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80.

82. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 81, wherein said anti-DPP3 monoclonal antibody or monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment.

83. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 82, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

84. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to embodiments 54 to 82, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it, or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

85. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain of said anti- ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156) : NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain of said anti-ADM antibody or anti-ADM antibody fragment comprises at least one CDR selected from the group comprising the sequences:

CDR1 (SEQ ID No: 158): RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159): KVSNRFS and/or

CDR3 (SEQ ID No: 160): FQGSHFPYT or a sequence wherein one or two amino acids are exchanged from the original CDR sequences in at least one of the CDR sequences provided that the binding affinity to ADM is diminished by not more than 20%.

86. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain variable region sequence shown in any one of SEQ ID NO: 161 and 163 , and the monoclonal antibody The cloned antibody comprises the light chain variable region sequence shown in any one of SEQ ID NO: 162 , 164 and 165 , wherein the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 161 and the light chain variable region sequence shown in SEQ ID NO: 162, the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 164, or the monoclonal antibody preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 163 and the light chain variable region sequence shown in SEQ ID NO: 165.

87. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 167 and the light chain shown in SEQ ID NO: 166.

88. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 169 and the light chain shown in SEQ ID NO: 168.

89. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 171 and the light chain shown in SEQ ID NO: 170.

90. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody comprises the heavy chain sequence shown in SEQ ID NO: 173 and the light chain shown in SEQ ID NO: 172.

91. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 32 to 42, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequence:

(i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and

(b) the light chain variable region of the monoclonal antibody or antibody fragment comprises the following CDR sequence:

(i) RAX7 Xs GIX9 X10 YLA, where X7 is selected from amino acids S or A, Xs is selected from amino acids Q or E, X9 is selected from amino acids S or G, X10 is selected from amino acids S or E, (ii) DXn SX12 X13 X14 X15, where Xu is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, X13 is selected from amino acids L or V, X14 is selected from amino acids E or D, X15 is selected from amino acids T or A,

(iii) QQYDX16 LX17 LXig, where Xi6 is selected from amino acids N or D, X17 is selected from amino acids P or D, Xis is selected from amino acids T or S.

92. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises HCDR1, HCDR2 and HCDR3 sequences, wherein the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 174, 182 and 186, and the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 175, 180, 185 and 189, and the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 176 and 181, and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises LCDR1, LCDR2 and LCDR3 sequences, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 177, 183 and 184, and the LCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 178, 187, 188 and 190 , and the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 179 , 191 and 192.

93. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYNGN (as shown in SEQ ID NO: 175),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178), (iii) QQYDNLPLT (shown in SEQ ID NO: 179).

94. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRSGGSFDI (as shown in SEQ ID NO: 176), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

95. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 or 194 , and the light chain variable region sequence as shown in SEQ ID NO: 200, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 193 and the light chain variable region sequence as shown in SEQ ID NO: 200 , or wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 194, and the light chain variable region sequence as shown in SEQ ID NO: 200.

96. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

97. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

98. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182), (ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RAAEGIGSYLA (as shown in SEQ ID NO: 184),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

99. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYSGN (as shown in SEQ ID NO: 185),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASEGISEYLA (as shown in SEQ ID NO: 183),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

100. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and (b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

101. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

102. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences: (i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNVDT (as shown in SEQ ID NO: 188),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

103. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DVSILDA (as shown in SEQ ID NO: 187),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179).

104. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTSY (as shown in SEQ ID NO: 174),

(ii) SPYTGK (as shown in SEQ ID NO: 189),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DTSDLDT (as shown in SEQ ID NO: 190),

(iii) QQYDNLPLT (shown in SEQ ID NO: 179). 105. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTHY (as shown in SEQ ID NO: 186),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLDLT (as shown in SEQ ID NO: 191).

106. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein

(a) the heavy chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) GYTFTQY (as shown in SEQ ID NO: 182),

(ii) SAYQGN (as shown in SEQ ID NO: 180),

(iii) EGRWGGSFNI (as shown in SEQ ID NO: 181), and

(b) the light chain variable region of the monoclonal antibody or monoclonal antibody fragment comprises the following CDR sequences:

(i) RASQGISSYLA (as shown in SEQ ID NO: 177),

(ii) DASNLET (as shown in SEQ ID NO: 178),

(iii) QQYDDLPLS (shown in SEQ ID NO: 192).

107. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiment 91, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the monoclonal antibody or monoclonal antibody fragment comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 to 199, the light chain variable region sequence shown in any one of SEQ ID NO: 200 to 207, wherein the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence as shown in SEQ ID NO: 195 and the light chain variable region sequence as shown in SEQ ID NO: 200, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 202, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 197 and the light chain variable region sequence shown in SEQ ID NO: 201, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 204, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 203, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 199 and the light chain variable region sequence shown in SEQ ID NO: 205, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 198 and the light chain variable region sequence shown in SEQ ID NO: 206, or the monoclonal antibody or monoclonal antibody fragment preferably comprises the heavy chain variable region sequence shown in SEQ ID NO: 196 and the light chain variable region sequence shown in SEQ ID NO: 207.

108. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 107, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds.

109. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 108, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti- DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70.

110. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 109, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti- DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71.

111. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 110, wherein said anti-DPP3 antibody is a monoclonal antibody or monoclonal antibody fragment.

112. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 111, wherein the complementarity determining regions (CDRs) in the heavy chain of said anti- DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80.

113. An anti- ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 112, wherein said anti-DPP3 monoclonal antibody or anti-DPP3 monoclonal antibody fragment is a humanized monoclonal antibody or humanized monoclonal antibody fragment. 114. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 113, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 81 and SEQ ID NO: 82, respectively, more particularly such fragments are Fab fragments.

115. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to embodiments 85 to 113, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence: SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it or fragments thereof comprising the CDRs as defined herein and comprising at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, preferably at least 95%, of SEQ ID NO: 208 and SEQ ID NO: 209, respectively, more particularly such fragments are Fab fragments.

The present invention is further described by reference to the following non-limiting Figures.

Figure Description

Fig. 1 A-D: Effect on DPP3 activity dependent on dose-dependent addition of Angiotensin II (panel A), ADM (panel B), ADM-Gly (panel C), and ADM fragment 1-10 (panel D). Relative fluorescence units (RFU) developing over time from incubation of DPP3 in the presence of various effector concentrations with the fluorogenic substrate Arg-Arg- -naphthylamide (100 pM) are shown. RFU are plotted against time points of measurement after start of incubation. DPP3 activity was defined as the slope of RFU over time as determined by simple linear regression. Fig. 2 A-D: Inhibition of DPP3 activity dependent on dose-dependent addition of Angiotensin II (panel A), ADM (panel B), ADM-Gly (panel C), and ADM fragment 1-10 (panel D).

Fig- 3: Influence of effectors on DPP3 activity. Effectors were added at a concentration of 10 pM. Ang II = Angiotensin II).

Fig. 4: Effect of injection of ADM-Gly in healthy rats on DPP3 activity measured in plasma.

Fig. 5 A-B: Relative inhibition of DPP3 activity dependent on dose-dependent addition of anti- ADM antibody in the presence of 10 pM ADM (panel A), and ADM-Gly (panel B). The inhibition achieved with 10 pM ADM and ADM-gly, respectively, was defined as 100% inhibition, and inhibition measured in the presence of anti-ADM antibody was related to this.

Fig. 6: Influence of ADM and ADM-Gly (at 10 pM each) in the absence or presence of anti-ADM antibody (“Ab”, at 1 rng/rnL) on DPP3 activity. Control consists of Arg-Arg-BNA (Arg-Arg-B- Naphthylamide) without the addition of peptides or antibody.

Fig. 7: Inhibition curve of native DPP3 from blood cells with inhibitory antibody AK1967. Inhibition of DPP3 by a specific antibody is concentration dependent, with an IC50 at ~15 ng/ml when analysed against 15 ng/ml DPP3.

Fig. 8: Association and dissociation curve of the AK1967-DPP3 binding analysis using Octet. AK1967 loaded biosensors were dipped into a dilution series of recombinant GST-tagged human DPP3 (100, 33.3, 11.1, 3.7 nM) and association and dissociation monitored.

Fig- 9: Western Blot of dilutions of blood cell lysate and detection of DPP3 with AK1967 as primary antibody.

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1726-1734. https://doi.org/10.1056/NEJMral208943

Examples

Example 1 - Influence of mature ADM and ADM-Gly on DPP3 activity

The effect of peptides mature ADM and ADM-Gly on DPP3 activity was tested in vitro.

DPP3 activity was measured using a soluble activity assay. In brief, a fluorogenic substrate (Arg-Arg- P-naphthylamide) was incubated with a constant concentration of DPP3, and fluorescence of P- naphthylamine continuously released by the turnover of the substrate was detected over a period of 60 minutes. The effect of addition of various concentrations of mature ADM and ADM-Gly was investigated. Angiotensin II, a known substrate of DPP3, served as positive control for the inhibition of DPP3 activity.

In more detail, the DPP3 activity was determined as follows:

Peptides were purchased from: Adrenomedullin human 1-52 (mature-ADM) (Peptides & Elephants EP 10779), ADM-Gly: (Peptides & Elephants EP 11653), ADM fragment 1-10 (Peptides & Elephants EPl 8946), Angiotensin II: Peptides & Elephants EP 15409. Peptides were dissolved and diluted as required in purified water. Purified human DPP3 was obtained from 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany.

The following solutions were prepared:

50 ng/mL purified, native human DPP3 in TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C) Mature ADM at following concentrations in ultra purified water: 830; 400; 100; 40; 10; 4; 1 M or pure water for 0 pM

ADM-Gly at following concentrations in ultra purified water: 821; 400; 100; 40; 10; 4; 1 pM or pure water for 0 pM

Angiotensin II at following concentrations in ultra purified water: 4000; 2000; 1000; 100; 10; 1; 0.1 pM or pure water for 0 pM

ADM fragment 1-10 at following concentrations in ultra purified water: 4000; 2000; 1000; 40; 10; 1 ; 0.1 pM or pure water for 0 pM

125 pM Arg-Arg-P-naphthylamide substrate solution (Bachem #K-1085) in TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C)

Dilutions of pure fiNA (Beta-Naphtylamine; Sigma- Aldrich #31618) in purified water were used as calibrators (0.6; 2; 5; 16; 46; 134 pM). Reactions were run in nonbinding, uncoated, black 96 well microplates (Greiner Bio-One #7635165).

Calibrators: 10 pL of the respective calibrator were pipetted in duplicates, followed by 10 pL pure water and 80pL TRIS/HCl-buffer (50 mM TRIS/HC1 pH = 8.3 at 25 °C) Samples: 10 pL of DPP3 were pipeted in duplicates into one side of the wells, afterwards 10 pL mature- ADM, ADM-Gly, ADM fragment 1-10 or Angiotensin II were pipeted in duplicates into the other side of the wells (no mixing to minimize possible inactivation of DPP3 due to strong pH changes). As a negative control, 10 pL TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C) were pipeted in duplicates into one side of the wells, afterwards 10 pL mature ADM, ADM-Gly, ADM fragment 1-10 or Angiotensin II were pipeted in duplicates into the other side of the wells. Afterwards 80 pl of substrate solution was added to each well.

Immediately after pipeting the kinetic measurement was started and the relative fluorescence units (RFU) (excitation at 340 nm and emission at 410 nm) were measured using a fluorescence plate reader (SpectraMax ID5; Molecular Devices).

The measurement was performed at 37 °C from t=0 every 10 minutes for 1 hour.

Raw data were evaluated as follows: Raw Data (mean RFU over time) were ploted, and the slope [RFU/min] was determined by linear regression fiting (R² > 0.95). The determined RFU/min were converted to pmol/min as follows: From the P-naphthylamine calibrator solutions, the RFU were measured. By linear regression of these data (forced through origin), it was determined how much RFU are generated per amount of P-naphthylamine, e.g. RFU/pmol. Using this factor, the activity measured for the samples in RFU/min was converted into pmol/min.Calculation of Inhibition: Inhibition (%) = 100-(activity only DPP3 / activity DPP3 + inhibitor) *100Plots of measured DPP3 activity (relative fluorescence units developing over time) in the presence of various effector concentrations are shown in Figures 1A to ID. Plots of effector dose-dependent inhibition of DPP3 activity are shown in Figures 2A to 2D. 50% Inhibition of the maximal DPP3 activity (IC50) was achieved with 8.0 pM Angiotensin II, 7.0 pM mature ADM, 7.1 pM ADM-Gly or 12.5 pM ADM fragment 1-10, respectively (Figure 2). The DPP3 activity measured after addition of 10 pM each of Angiotensin II, mature ADM, ADM-Gly or ADM fragment 1-10, respectively, relative to the DPP3 activity measured in the absence of effectors is shown in Table 2 and graphically represented in Figure 3.

Table 2: Influence of effectors on DPP3 activity. Effectors were added at a concentration of 10 pM.

Surprisingly, it was found that both mature ADM (SEQ ID NO: 83) and ADM-Gly (SEQ ID NO: 6), as well as the N-terminal ADM fragment 1-10 (SEQ ID NO: 49) have a pronounced inhibitory effect on DPP3 activity.

Example 2 - Infusion of ADM-Gly in rats and its effect on DPP3 activity in plasma

ADM-Gly (synthetic human 1-53 ADM-Gly (SEQ ID NO: 6) was infused in healthy rats (male Sprague Dawley rats; average bodyweight of 353 g) at a rate of 432 ng/(kg*min) over 150 min, resulting in a total dosage of 64.8 pg/kg. Animals were housed in temperature-controlled rooms (20-24°C) and maintained in a 12h light/ 12h dark cycle. Animals were fed ad libitum before and during the study. The infusion was performed for 2.5 hours at a rate of 12.5 pl/min via a jugular vein catheter with n=3 animals per group. Rats were treated twice with Carprofen (5 mg/kg) directly after catheterization and the day after. The catheter was rinsed daily with heparin. Blood was drawn before the infusions, as well as at 0.5h, Ih, 2h, 3h, 4h and 6h after infusions were started. No signs of toxicity or any behavioural changes were observed during the observation period.

The inhibitory effect of ADM/ADM-Gly on the DPP3 activity was not only observed in vitro, but also in vivo'. DPP3 activity was measured in plasma obtained from healthy rats prior to and after administration of ADM-Gly. The administration of ADM-Gly resulted in a reduction of DPP3 activity by 30% (Figure 4).

The data clearly demonstrate that ADM and related peptides inhibit DPP3 activity and thus could be used for the treatment of a patient in need thereof, who suffer from pathological elevation of circulating DPP3 (cDPP3) concentration and the associated consequences.

Example 3 - Effect of anti- ADM antibody on inhibitory effect of ADM/ADM-Gly on DPP3 activity

It was further assessed, how an antibody directed against the N-terminal moiety of ADM/ADM-Gly would affect the ADM-/ADM-Gly-induced inhibition of DPP3 activity in vitro. To this end, the DPP3 activity was measured after addition of 10 pM each of ADM, and ADM-Gly, respectively, either in the absence or presence of anti-ADM antibody. As an example of anti- ADM antibody, enibarcimab, a humanized anti-ADM antibody binding to the N-terminal part of ADM or ADM-Gly, was used. Measured DPP3 activities in presence of anti-ADM antibody were related to the DPP3 activity measured in the absence of anti-ADM antibody.

The DPP3 activity was determined as follows: A fluorogenic substrate (Arg-Arg-P-naphthylamide) was mixed with DPP3 and a fluorescence-based measurement of released P-naphthylamine was started immediately. The kinetic measurement was over a period of 60min at 10 min intervals and set against a calibration curve of BNA.

Following solutions were prepared:

50 ng/mL purified, native human DPP3 (4TEEN4 Pharmaceuticals, Hennigsdorf, Germany) in TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C)

100 pM mature ADM (Adrenomedullin human 1-52, peptide & elephants EP 10779) in ultra purified water

100 pM ADM-Gly (peptide & elephants EP11653) in ultra purified water

143 pM Arg-Arg-P-naphthylamide substrate solution (Bachem #K-1085) in TRIS/HC1 buffer (50 mM TRIS/HC1 pH = 8.3 at 25 °C)

Anti-ADM-antibody Enibarcimab (Hblzel Diagnostika Handels GmbH, Cologne, Germany (www.hoelzel-biotech.com/en/antibody-b689301-lmg-anti-human-admenibarcimab.html) at following concentrations in lx PBS (137 mM NaCl; 2.7 mM KC1; 10 mM; Na2HPC>4*2H2O; 1.8 mM KH₂PO₄ pH 7.4): 15,000, 10,000, 5,000, 1,000, 100, 10, 1, 0.1, 0.01, 0 pg/mL

Dilutions of pure BNA (Beta-Naphtylamine; Sigma- Aldrich #31618) in purified water were used as calibrators (0.6; 2; 5; 16; 46; 134 pM). Reactions were run in nonbinding, uncoated, black 96 well microplates (Greiner Bio-One #7635165).

Samples: 25 pL mature ADM or ADM-Gly peptide and 25 pL anti-ADM antibody were mixed and incubated for 30 minutes at room temperature. 10 pL of DPP3 were pipetted in duplicates into one side of the wells, afterwards 20 pL of peptide-antibody mixture were pipetted in duplicates into the other side of the wells (no mixing to minimize possible inactivation of DPP3 due to strong pH changes). 70 pl of substrate solution were added to each well.

Calibrators : 10 pL of the respective calibrator were pipetted in duplicates, followed by 10 pL pure water, 10 pL lx PBS and 70 pL TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C). Immediately after pipetting the kinetic measurement was started and the relative fluorescence units (RFU) (excitation at 340 nm and emission at 410 nm) were measured using a fluorescence plate reader (SpectraMax ID5; Molecular Devices).

The measurement was performed at 37 °C from t=0 every 10 minutes for 1 hour. Raw data were evaluated as follows:

Raw Data (mean RFU over time) were plotted, and the slope [RFU/min] was determined by linear regression fitting (R² > 0.95). The determined RFU/min were converted to pmol/min as follows: From the P-naphthylamine calibrator solutions, the RFU were measured. By linear regression of these data (forced through origin), it was determined how much RFU are generated per amount of P-naphthylamine, e.g. RFU/pmol. Using this factor, the activity measured for the samples in RFU/min was converted into pmol/min.

Calculation of inhibition: Inhibition (%) = 100-(activity _Oni_y DPPS I activity DPP3 + inhibitor) * 100

Surprisingly, the addition of anti-ADM antibody reversed the inhibitory effect of ADM/ADM-Gly on DPP3 activity in a dose-dependent manner (Figure 5A and 5B). In this experimental setting, complete reversal of ADM/ADM-Gly-induced inhibition of DPP3 activity was achieved with 1 mg/mL anti-ADM antibody (Figure 6).

The likely mechanism behind this reversal effect is that the anti-ADM antibody binds to ADM/ADM- Gly interacting with DPP3, and thereby leads to a detachment of ADM/ADM-Gly from DPP3.

This surprising finding has therapeutic implications: Subgroup analyses of the AdrenOSS-2 clinical trial suggest that septic shock patients could be adversely affected by treatment with enibarcimab, when DPP3 concentrations are or become pathologically elevated. Only upon exclusion of patients with elevated pre-dose cDPP3 concentrations, a beneficial effect of enibarcimab on the 28-day mortality risk of these patients was observed (Lier et al., 2022).

If in a subgroup of AdrenOSS-2 defined by having a low pre-dose cDPP3 concentration a much stronger beneficial treatment effect of enibarcimab is observed than in the entire population (full analysis set), it is inherently clear that in the complementary subgroup, e.g. those patients with high pre-dose cDPP3 concentrations, the treatment effect of enibarcimab must be worse than in the entire population.

The published data even suggest that treatment with enibarcimab of patients with pathologically elevated pre-dose cDPP3 concentrations could possibly put these patients at risk for increased 28-day mortality compared to placebo.

The data described in the current invention provide a mechanistic explanation for this: Septic shock patients typically exhibit elevated ADM/ADM-Gly concentrations. This was one inclusion criterion in AdrenOSS-2. In the absence of anti-ADM antibody, this ADM/ADM-Gly to a certain extent would bind to and inhibit circulating DPP3. Now, upon administration of anti-ADM antibody, DPP3 -bound ADM/ADM-Gly gets detached from DPP3, and thereby formerly inhibited DPP3 gets activated. This, in turn, if DPP3 activity/concentration is sufficiently high, leads to the known adverse effects that result from the DPP3-induced degradation of Angiotensin II (Deniau et al., 2020). Apractical consequence of this understanding is that a DPP3 binder can be used in the treatment of a patient in need thereof that is intended to be treated or was pre-treated with an anti-ADM antibody. Example 4 - Methods for the measurement of DPP3 protein and DPP3 activity

Generation of antibodies and determination DPP3 binding ability: Several murine antibodies were produced and screened by their ability of binding human DPP3 in a specific binding assay (see Table 3).

Peptides/ conjugates for immunization:

DPP3 peptides for immunization were synthesized, see Table 3, (JPT Technologies, Berlin, Germany) with an additional N-terminal cystein (if no cystein is present within the selected DPP3 -sequence) residue for conjugation of the peptides to Bovine Serum Albumin (BSA). The peptides were covalently linked to BSA by using Sulfolink-coupling gel (Perbio-science, Bonn, Germany). The coupling procedure was performed according to the manual of Perbio. Recombinant GST-hDPP3 was produced by USBio (United States Biological, Salem, MA, USA).

Immunization of mice, immune cell fusion and screening:

Balb/c mice were intraperitoneally (i.p.) injected with 84 pg GST-hDPP3 or 100 pg DPP3-peptide-BSA- conjugates at day 0 (emulsified in TiterMax Gold Adjuvant), 84 pg or 100 pg at day 14 (emulsified in complete Freund’s adjuvant) and 42 pg or 50 pg at day 21 and 28 (in incomplete Freund’s adjuvant). At day 49 the animal received an intravenous (i.v.) injection of 42 pg GST-hDPP3 or 50 pg DPP3-peptide- BSA-conjugates dissolved in saline. Three days later the mice were sacrificed and the immune cell fusion was performed.

Splenocytes from the immunized mice and cells of the myeloma cell line SP2/0 were fused with 1 ml 50% polyethylene glycol for 30 s at 37°C. After washing, the cells were seeded in 96-well cell culture plates. Hybrid clones were selected by growing in HAT medium [RPMI 1640 culture medium supplemented with 20% fetal calf serum and HAT-Supplement]. After one week, the HAT medium was replaced with HT Medium for three passages followed by returning to the normal cell culture medium. The cell culture supernatants were primarily screened for recombinant DPP3 binding IgG antibodies two weeks after fusion. Therefore, recombinant GST-tagged hDPP3 (USBiologicals, Salem, USA) was immobilized in 96-well plates (100 ng/ well) and incubated with 50 pl cell culture supernatant per well for 2 hours at room temperature. After washing of the plate, 50 pl / well POD-rabbit anti mouse IgG was added and incubated for 1 h at RT. After a next washing step, 50 pl of a chromogen solution (3,7 mM o-phenylen-diamine in citrate/ hydrogen phosphate buffer, 0.012% H2O2) were added to each well, incubated for 15 minutes at RT and the chromogenic reaction stopped by the addition of 50 pl 4N sulfuric acid. Absorption was detected at 490 mm. The positive tested microcultures were transferred into 24- well plates for propagation. After retesting the selected cultures were cloned and re-cloned using the limiting-dilution technique and the isotypes were determined. Mouse monoclonal antibody production

Antibodies raised against GST-tagged human DPP3 or DPP3 -peptides were produced via standard antibody production methods (Marx et al. 1997} and purified via Protein A. The antibody purities were > 90% based on SDS gel electrophoresis analysis.

Characterization of antibodies - binding to hDPP3 and/ or immunization peptide

To analyse the capability of DPP3/ immunization peptide binding by the different antibodies and antibody clones a binding assay was performed:

Solid phase: Recombinant GST-tagged hDPP3 (SEQ ID NO: 70) or a DPP3 peptide (immunization peptide, SEQ ID NO: 71) was immobilized onto a high binding microtiter plate surface (96- Well polystyrene microplates, Greiner Bio-One international AG, Austria, 1 pg/well in coupling buffer [50 mM Tris, 100 mM NaCl, pH7,8], Ih at RT). After blocking with 5% bovine serum albumin, the microplates were vacuum dried.

Labelling procedure (tracer):

100 pg (100 pl) of the different antiDPP3 antibodies (detection antibody, 1 mg/ ml in PBS, pH 7.4) were mixed with 10 pl acridinium NHS-ester (1 mg/ml in acetonitrile, InVent GmbH, Germany; EP 0 353 971) and incubated for 30 min at room temperature. Labelled antiDPP3 antibody was purified by gelfiltration HPLC on Shodex Protein 5 pm KW-803 (Showa Denko, Japan). The purified labelled antibody was diluted in assay buffer (50 mrnol/1 potassium phosphate, 100 mrnol/1 NaCl, 10 mmol/1 Na2-EDTA, 5 g/1 bovine serum albumin, 1 g/1 murine IgG, 1 g/1 bovine IgG, 50 pmol/1 amastatin, 100 pmol/1 leupeptin, pH 7.4). The final concentration was approx. 5-7*10⁶ relative light units (RLU) of labelled compound (approx. 20 ng labelled antibody) per 200 pl. acridinium ester chemiluminescence was measured by using a Centro LB 960 luminometer (Berthold Technologies GmbH & Co. KG). hDPP3 binding assay: the plates were filled with 200 pl of labelled and diluted detection antibody (tracer) and incubated for 2-4 h at 2-8 °C. Unbound tracer was removed by washing 4 times with 350 pl washing solution (20 mM PBS, pH 7.4, 0.1 % Triton X-100). Well-bound chemiluminescence was measured by using the Centro LB 960 luminometer (Berthold Technologies GmbH & Co. KG).

Characterization of antibodies - hDPP3 -inhibition analysis

To analyse the capability of DPP3 inhibition by the different antibodies and antibody clones a DPP3 activity assay with known procedure (Jones et al., 1982) was performed. Recombinant GST-tagged hDPP3 was diluted in assay buffer (25 ng/ ml GST-DPP3 in 50 mM Tris-HCl, pH7,5 and 100 pM ZnCh) and 200 pl of this solution incubated with 10 pg of the respective antibody at room temperature. After 1 hour of pre-incubation, fluorogenic substrate Arg-Arg-pNA (20 pl, 2mM) was added to the solution and the generation of free PNA over time was monitored using the Twinkle LB 970 microplate fluorometer (Berthold Technologies GmbH & Co. KG) at 37 °C. Fluorescence of PNA is detected by exciting at 340 nm and measuring emission at 410 nm. Slopes (in RFU/ min) of increasing fluorescence of the different samples are calculated. The slope of GST-hDPP3 with buffer control is appointed as 100 % activity. The inhibitory ability of a possible capture-binder is defined as the decrease of GST-hDPP3 activity by incubation with said capture-binder in percent.

The following table 3 represents a selection of obtained antibodies and their binding rate in Relative Light Units (RLU) as well as their relative inhibitory ability (%; table 3). The monoclonal antibodies raised against the below depicted DPP3 regions, were selected by their ability to bind recombinant DPP3 and/ or immunization peptide, as well as by their inhibitory potential.

All antibodies raised against the GST-tagged, full-length form of recombinant hDPP3 show a strong binding to immobilized GST-tagged hDPP3. Antibodies raised against the SEQ ID NO: 71 peptide bind as well to GST-hDPP3. The SEQ ID NO: 70 antibodies also strongly bind to the immunization peptide.

The development of a luminescence immunoassay for the quantification of DPP3 protein concentrations (DPP3-LIA) as well as an enzyme capture activity assay for the quantification of DPP3 activity (DPP3- ECA) have been described recently (Rehfeld et al. 2019. JALM 3(6): 943-953). which is incorporated here in its entirety by reference.

Table 3: List of antibodies raised against full-length or sequences of hDPP3 and their ability to bind hDPP3 (SEQ ID NO: 70) or immunization peptide (SEQ ID NO: 71) in RLU, as well as the maximum inhibition of recombinant GST-hDPP3. Example 5 - Development of Procizumab

Antibodies raised against SEQ ID NO: 71 were characterized in more detail (epitope mapping, binding affinities, specificity, inhibitory potential). Here the results for clone 1967 of SEQ ID NO: 71 (AK1967; “Procizumab”) are shown as an example.

Determination of AK1967 epitope on DPP3:

For epitope mapping of AK1967 a number of N- or C-terminally biotinylated peptides were synthesized (peptides & elephants GmbH, Hennigsdorf, Germany). These peptides include the sequence of the full immunization peptide (SEQ ID NO: 71) or fragments thereof, with stepwise removal of one amino acid from either C- or N-terminus (see table 4 for a complete list of peptides).

High binding 96 well plates were coated with 2 p.g Avidin per well (Greiner Bio-One international AG, Austria) in coupling buffer (500 mM Tris-HCl, pH 7.8, 100 mM NaCl). Plates were then washed and filled with specific solutions of biotinylated peptides (10 ng/ well; buffer - lxPBS with 0.5% BSA).

Anti-DPP3 antibody AK1967 was labelled with a chemiluminescence label according to Example 4.

The plates were filled with 200 pl of labelled and diluted detection antibody (tracer) and incubated for 4 h at room temperature. Unbound tracer was removed by washing 4 times with 350 pl washing solution (20 mM PBS, pH 7.4, 0.1 % Triton X-100).

Well-bound chemiluminescence was measured by using the Centro LB 960 luminometer (Berthold Technologies GmbH & Co. KG). Binding of AK1967 to the respective peptides is determined by evaluation of the relative light units (RLU). Any peptide that shows a significantly higher RLU signal than the unspecific binding of AK1967 is defined as AK1967 binder. The combinatorial analysis of binding and non-binding peptides reveals the specific DPP3 epitope of AK1967.

Determination of binding affinities using Octet:

The experiment was performed using Octet Red96 (ForteBio). AK1967 was captured on kinetic grade anti-humanFc (AHC) biosensors. The loaded biosensors were then dipped into a dilution series of recombinant GST-tagged human DPP3 (100, 33.3, 11.1, 3.7 nM). Association was observed for 120 seconds followed by 180 seconds of dissociation. The buffers used for the experiment were assay buffer (PBS with 0.1% BSA, 0.02% Tween-21), regeneration buffer (10 m Glycine buffer (pH 1.7)) and neutralization buffer (PBS with 0.1% BSA, 0.02% Tween-21), respectively. Kinetic analysis was performed using a 1 : 1 binding model and global fitting.

Western Blot analysis of Binding specificity of AK1967:

Blood cells from human EDTA-blood were washed (3x in PBS), diluted in PBS and lysed by repeated freeze-thaw-cycles. The blood cell lysate had a total protein concentration of 250 jig/ml, and a DPP3 concentration of 10 gg/ml. Dilutions of blood cell lysate (1:40, 1:80, 1:160 and 1:320) and of purified recombinant human His-DPP3 (31.25-500 ng/ml) were subjected to SDS-PAGE and Western Blot. The blots were incubated in 1.) blocking buffer (IxPBS-T with 5% skim milk powder), 2.) primary antibody solution (AK1967 1 :2.000 in blocking buffer) and 3.) HRP labelled secondary antibody (goat anti mouse IgG, 1:1.000 in blocking buffer). Bound secondary antibody was detected using the Amersham ECL Western Blotting Detection Reagent and the Amersham Imager 600 UV (both fan GE Healthcare).

DPP3 inhibition assay: To analyse the capability of DPP3 inhibition by AK1967 a DPP3 activity assay with known procedure (Jones et al., 1982) was performed as described in example 6. The inhibitory ability AK1967 is defined as the decrease of GST-hDPP3 activity by incubation with said antibody in percent. The resulting lowered DPP3 activities are shown in an inhibition curve in Figure 7.

Epitope mapping: The analysis of peptides that AK1967 binds to and does not bind to revealed the DPP3 sequence INPETG (SEQ ID NO: 72) as necessary epitope for AK1967 binding (see table 4).

Binding affinity: AK1967 binds with an affinity of 2.2*1 O'⁹ M to recombinant GST-hDPP3 (kinetic curves see Figure 8).

Table 4: Peptides used for Epitope mapping of AK1967. Specificity and inhibitory potential:

The only protein detected with AK1967 as primary antibody in lysate of blood cells was DPP3 at 80 kDa (Figure 9). The total protein concentration of the lysate was 250 pg/ml whereas the estimated DPP3 concentration is about 10 pg/ml. Even though there is 25 times more unspecific protein in the lysate, AK1967 binds and detects specifically DPP3 and no other unspecific binding takes place.

AK1967 inhibits 15 ng/ ml DPP3 in a specific DPP3 activity assay with an IC50 of about 15 ng/ml (Figure 7).

Chimerization/ Humanization:

The monoclonal antibody AK 1967 (“Procizumab”), with the ability of inhibiting DPP3 activity by 70 %, was chosen as possible therapeutic antibody and was also used as template for chimerization and humanization.

Humanization of murine antibodies may be conducted according to the following procedure:

For humanization of an antibody of murine origin the antibody sequence is analysed for the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen. Based on structural modelling an appropriate FR of human origin is selected and the murine CDR sequences are transplanted into the human FR. Variations in the amino acid sequence of the CDRs or FRs may be introduced to regain structural interactions, which were abolished by the species switch for the FR sequences. This recovery of structural interactions may be achieved by random approach using phage display libraries or via directed approach guided by molecular modelling (Almagro and Fransson, 2008. Humanization of antibodies. Front Biosci. 13:1619-33).

With the above context, the variable region can be connected to any subclass of constant regions (IgG, IgM, IgE. IgA), or only scaffolds, Fab fragments, Fv, Fab and F(ab)2. The murine antibody variant contains an IgG2a backbone. For chimerization and humanization a human IgGlk backbone was used.

For epitope binding the Complementarity Determining Regions (CDRs) are of importance. The CDRs for the heavy chain and the light chain of the murine anti-DPP3 antibody (AK1967; “Procizumab”) are shown in SEQ ID NO: 76, SEQ ID NO: 77 and SEQ ID NO: 78 for the heavy chain and SEQ ID NO: 79, sequence KVS and SEQ ID NO: 80 for the light chain, respectively.

Sequencing of the anti-DPP3 antibody (AK1967; “Procizumab”) revealed an antibody heavy chain variable region (H chain) according to SEQ ID NO: 81 and an antibody light chain variable region (L chain) according to SEQ ID NO: 82.

Example 6 - Generation of anti-NT-ADM Antibodies and characterization

Several human and murine antibodies directed to NT-ADM were produced and their affinity constants were determined (see tables 5 and 6). It should be emphasized that the antibodies, antibody fragments and non-Ig scaffolds of the example portion in accordance with the invention are binding to ADM, and thus should be considered as anti-ADM antibodies/ antibody fragments/ non-Ig scaffolds.

Peptides / conjugates for Immunization:

Peptides for immunization were synthesized, see Table 5, (JPT Technologies, Berlin, Germany) with an additional N-terminal Cystein (if no Cystein is present within the selected ADM-sequence) residue for conjugation of the peptides to Bovine Serum Albumin (BSA). The peptides were covalently linked to BSA by using Sulfolink-coupling gel (Perbio-science, Bonn, Germany). The coupling procedure was performed according to the manual of Perbio.

Mouse monoclonal antibody production:

A Balb/c mouse was immunized with lOOpg Peptide-BSA-Conjugate at day 0 and 14 (emulsified in lOOpl complete Freund’s adjuvant) and 50pg at day 21 and 28 (in lOOpl incomplete Freund’s adjuvant). Three days before the fusion experiment was performed, the animal received 5O ,g of the conjugate dissolved in 1 OOpl saline, given as one intraperitoneal and one intra-venous injection. Splenocytes from immunized mouse and cells of the myeloma cell line SP2/0 were fused with 1ml 50% polyethylene glycol for 30s at 37°C. After washing, the cells were seeded in 96-well cell culture plates.

Hybrid clones were selected by growing in HAT medium [RPMI 1640 culture medium supplemented with 20% fetal calf serum and HAT-Supplement], After two weeks the HAT medium is replaced with HT Medium for three passages followed by returning to the normal cell culture medium. Cell culture supernatants were primary screened for antigen specific IgG antibodies three weeks after fusion. The positive tested microcultures were transferred into 24-well plates for propagation. After retesting, the selected cultures were cloned and re-cloned using the limiting-dilution technique and isotypes were determined (see also Lane, R.D. 1985. J. Immunol. Meth. 81: 223-228; Ziegler et al. 1996. Harm. Metab. Res. 28: 11-15).

Antibodies were produced via standard antibody production methods (Marx et al, 1997. Monoclonal Antibody Production, ATLA 25, 121) and purified via Protein A. The antibody purities were > 95% based on SDS gel electrophoresis analysis.

Affinity Constants: To determine the affinity of the antibodies to NT- ADM, the kinetics of binding of ADM to immobilized antibody was determined by means of label-free surface plasmon resonance using a Biacore 2000 system (GE Healthcare Europe GmbH, Freiburg, Germany). Reversible immobilization of the antibodies was performed using an anti-mouse Fc antibody covalently coupled in high density to a CM5 sensor surface according to the manufacturer's instructions (mouse antibody capture kit; GE Healthcare). (Lorenz et al. 2011. Antimicrob Agents Chemother 55(1): 165-173).

The effect of ADM-antibodies on ADM-bioactivity was tested in a human recombinant Adrenomedullin receptor cAMP functional assay (Adrenomedullin Bioassay) as described in WO2021170838. The monoclonal antibodies were raised against the below depicted NT-ADM regions of human and murine ADM, respectively. The following table 5 represents a selection of obtained antibodies used in further experiments. Selection was based on target region:

Table 5: NT- ADM immunization peptides.

Table 6: Further obtained monoclonal NT-ADM antibodies.

Generation of antibody fragments by enzymatic digestion:

The generation of Fab and F(ab)z fragments was done by enzymatic digestion of the murine full-length antibody NT-M. Antibody NT-M was digested using a) the pepsin-based F(ab)2 Preparation Kit (Pierce 44988) and b) the papain-based Fab Preparation Kit (Pierce 44985). The fragmentation procedures were performed according to the instructions provided by the supplier. Digestion was carried out in case of F(ab)2-fragmentation for 8h at 37°C. The Fab-fragmentation digestion was carried out for 16 h, respectively.

Procedure for Fab Generation and Purification:

The immobilized papain was equilibrated by washing the resin with 0.5 ml of Digestion Buffer and centrifuging the column at 5000 x g for 1 minute. The buffer was discarded afterwards. The desalting column was prepared by removing the storage solution and washing it with digestion buffer, centrifuging it each time afterwards at 1000 x g for 2 minutes. 0.5ml of the prepared IgG sample were added to the spin column tube containing the equilibrated Immobilized Papain. Incubation time of the digestion reaction was done for 16h on a tabletop rocker at 37°C. The column was centrifuged at 5000 x g for 1 minute to separate digest from the Immobilized Papain. Afterwards the resin was washed with 0.5ml PBS and centrifuged at 5000 x g for 1 minute. The wash fraction was added to the digested antibody that the total sample volume was 1.0ml. 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 storage solution (contains 0.02% sodium azide) and equilibrated by adding 2ml of PBS, centrifuge again for 1 minute and the flow-through discarded. The sample was applied to the column and resuspended by inversion. Incubation was done at room temperature with end-over-end mixing for 10 minutes. The column was centrifuged for 1 minute, saving the flow-through with the Fab fragments. (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).

Procedure for generation and purification of Ffab'fr Fragments: T he immobilized Pepsin was equilibrated by washing the resin with 0.5 ml of Digestion Buffer and centrifuging the column at 5000 x g for 1 minute. The buffer was discarded afterwards. The desalting column was prepared by removing the storage solution and washing it with digestion buffer, centrifuging it each time afterwards at 1000 x g for 2 minutes. 0.5ml of the prepared IgG sample were added to the spin column tube containing the equilibrated Immobilized Pepsin. Incubation time of the digestion reaction was done for 16h on a tabletop rocker at 37°C. The column was centrifuged at 5000 x g for 1 minute to separate digest from the Immobilized Papain. Afterwards the resin was washed with 0.5 mL PBS and centrifuged at 5000 x g for 1 minute.

The wash fraction was added to the digested antibody that the total sample volume was 1.0ml. 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 storage solution (contains 0.02% sodium azide) and equilibrated by adding 2 mL of PBS, centrifuge again for 1 minute and the flow-through discarded. The sample was applied to the column and resuspended by inversion. Incubation was done at room temperature with end-over-end mixing for 10 minutes. The column was centrifuged for 1 minute, saving the flow-through with the Fab fragments. (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).

NT-H-Antibody Fragment Humanization:

The antibody fragment was humanized by the CDR-grafting method (Jones et al. 1986. Nature 321, 522-525).

The following steps were done to achieve the humanized sequence:

Total RNA extraction: Total RNA was extracted from NT-H hybridomas using the Qiagen kit. First- round RT-PCR: QIAGEN® OneStep RT-PCR Kit (Cat No. 210210) was used. RT-PCR was performed with primer sets specific for the heavy and light chains. For each RNA sample, 12 individual heavy chain and 11 light chain RT-PCR reactions were set up using degenerate forward primer mixtures covering the leader sequences of variable regions. Reverse primers are located in the constant regions of heavy and light chains. No restriction sites were engineered into the primers.

Reaction Setup: 5x QIAGEN® OneStep RT-PCR Buffer 5.0 pl, dNTP Mix (containing 10 mM of each dNTP) 0.8 pl, Primer set 0.5 pl, QIAGEN® OneStep RT-PCR Enzyme Mix 0.8 pl, Template RNA 2.0 pl, RNase-free water to 20.0 pl, Total volume 20.0 pl PCR condition: Reverse transcription: 50°C, 30 min; Initial PCR activation: 95°C, 15 min Cycling: 20 cycles of 94°C, 25 sec; 54°C, 30 sec; 72°C, 30 sec; Final extension: 72°C, 10 min Second-round semi-nested PCR: The RT- PCR products from the first-round reactions were further amplified in the second-round PCR. 12 individual heavy chain and 11 light chain RT-PCR reactions were set up using semi-nested primer sets specific for antibody variable regions.

Reaction Setup: 2x PCR mix 10 pl; Primer set 2 pl; First-round PCR product 8 pl; Total volume 20 pl; Hybridoma Antibody Cloning Report PCR condition: Initial denaturing of 5 min at 95°C; 25 cycles of 95°C for 25 sec, 57°C for 30 sec, 68°C for 30 sec; Final extension is 10 min 68°C.

After PCR was finished, PCR reaction samples were run onto agarose gel to visualize DNA fragments amplified. After sequencing more than 15 cloned DNA fragments amplified by nested RT-PCR, several mouse antibody heavy and light chains have been cloned and appear correct. Protein sequence alignment and CDR analysis identifies one heavy chain and one light chain. After alignment with homologous human framework sequences the resulting humanized sequence for the variable heavy chain is the following: see Figure 5. As the amino acids on positions 26, 40 and 55 in the variable heavy chain and amino acid on position 40 in the variable light are critical to the binding properties, they may be reverted to the murine original. The resulting candidates are depicted below. (Padlan 1991. Mol. Immunol. 28, 489-498; Harris andBajorath.1995. Protein Sci. 4, 306-310).

Annotation for the antibody fragment sequences (SEQ ID NO: 60-67; 68 and 69): bold and underline are the CDR 1, 2, 3 chronologically arranged.

SEQ ID NO: 60 (AM-VH-C)

OVOLOQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYN EKFKGKATITADTSSNTAYMOLSSLTSEDSAVYYCTEGYEYDGFDYWGOGTTLTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

OVOLVOSGAEVKKPGSSVKVSCKASGYTFSRYWISWVROAPGOGLEWMGRILPGSGSTNY AOKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGOGTTVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SEQ ID NO: 62 (AM-VH2-E40)

OVOLVOSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGOGLEWMGRILPGSGSTNY

AOKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGOGTTVTVSSASTK

GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

OVOLVOSGAEVKKPGSSVKVSCKATGYTFSRYWISWVROAPGOGLEWMGEILPGSGSTNYA

OKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGOGTTVTVSSASTKG

PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW

TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

OVOLVOSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVROAPGOGLEWMGEILPGSGSTNY

AOKFOGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGOGTTVTVSSASTK

GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDOATISCRSSQSIVYSNGNTYLEWYLQKPGOSPKLLIYRVSNRFSGVP

DRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSfflPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQ

LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DWMTOSPLSLPVTLGOPASISCRSSQSIVYSNGNTYLNWFOQRPGOSPRRLIYRVSNRDSGV

PDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDE

QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD

YEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTOSPLSLPVTLGOPASISCRSSQSIVYSNGNTYLEWFOQRPGOSPRRLIYRVSNRDSGVP

DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ

LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 68 (enibarcimab heavy chain)

OVOLVOSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVROAPGOGLEWIGEILPGSGSTNYN

OKFOGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGOGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW

TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ

DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP

SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGK

SEQ ID NO: 70 (enibarcimab light chain)

DWLTOSPLSLPVTLGOPASISCRSSQSIVYSNGNTYLEWYLORPGOSPRLLIYRVSNRFSGVP

DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEO

LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

EKHKVYACEVTHQGLSSPVTKSFNRGEC

Example 7 - Influence of ADM fragments on DPP3 activity

The effect of peptides representing fragments of ADM, in particular C-terminally truncated variants of ADM, listed in Table 7 on DPP3 activity was tested in vitro.

Table 7: ADM fragments. Amino acid sequences and concentrations of the peptides, which led to a 50% inhibition of DPP3 activity in vitro (IC50) are shown.

DPP3 activity was measured using a soluble activity assay. In brief, a fluorogenic substrate (Arg-Arg- P-naphthylamide) was incubated with a constant concentration of DPP3, and fluorescence of P- naphthylamine continuously released by the turnover of the substrate was detected over a period of 60 minutes. The effect of addition of various concentrations of ADM fragments was investigated.

In more detail, the DPP3 activity was determined as follows:

All peptides were chemically synthesized and purchased from Peptides & Elephants (Hennigsdorf, Germany): Peptides were dissolved and diluted as required in purified water. Purified human DPP3 was obtained from 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany.

The following solutions were prepared:

50 ng/mL purified, native human DPP3 in TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C) ADM fragments at following concentrations in ultra purified water: 830; 400; 100; 40; 10; 4; 1 pM or pure water for 0 pM

125 pM Arg-Arg-P-naphthylamide substrate solution (Bachem #K-1085) in TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C)

Dilutions of pure BNA (Beta-Naphtylamine; Sigma- Aldrich #31618) in purified water were used as calibrators (0.6; 2; 5; 16; 46; 134 pM). Reactions were run in nonbinding, uncoated, black 96 well microplates (Greiner Bio-One #7635165).

Calibrators: 10 pL of the respective calibrator were pipetted in duplicates, followed by 10 pL pure water and 80 pL TRIS/HCl-buffer (50 mM TRIS/HC1 pH = 8.3 at 25 °C).

Samples: 10 pL of DPP3 were pipetted in duplicates into one side of the wells, afterwards 10 pL ADM fragments were pipetted in duplicates into the other side of the wells (no mixing to minimize possible inactivation of DPP3 due to strong pH changes). As a negative control, 10 pL TRIS/HC1 buffer (50 mM TRIS/HC1 pH 8.3 at 25 °C) were pipetted in duplicates into one side of the wells, afterwards 10 pL ADM fragments were pipetted in duplicates into the other side of the wells. Afterwards 80 pl of substrate solution was added to each well.

Immediately after pipetting, the kinetic measurement was started, and the relative fluorescence units (RFU) (excitation at 340 nm and emission at 410 nm) were measured using a fluorescence plate reader (SpectraMax ID5; Molecular Devices).

The measurement was performed at 37 °C from t=0 every 10 minutes for 1 hour. Raw data were evaluated as follows: Raw Data (mean RFU over time) were plotted, and the slope [RFU/min] was determined by linear regression fitting (R² > 0.95). The determined RFU/min were converted to pmol/min as follows: From the -naphthylamine calibrator solutions, the RFU were measured. By linear regression of these data (forced through origin), it was determined how much RFU are generated per amount of P-naphthylamine, e.g. RFU/pmol. Using this factor, the activity measured for the samples in RFU/min was converted into pmol/min. Calculation of Inhibition: Inhibition (%) = 100-(activity _Oni_y DPP3 I activity DPP3 + inhibit ) * 100. Plots of each ADM fragment dose-dependent inhibition of DPP3 were generated, and the concentration of each ADM fragment leading to 50% inhibition of the maximal DPP3 activity (IC50) was read from the curves. The IC50 concentrations determined for the ADM fragments are summarized in Table 7.

All ADM fragments tested had an inhibitory effect on DPP3 activity, which was similar to what had been observed previously for mature ADM (SEQ ID NO: 83) and ADM-Gly (SEQ ID NO: 6).

SEQUENCES

SEQ ID NO: 1 - pre-proADM (aa 1-185)

MKL VS VALMY LGSLAFLGAD TARLDVASEF RKKWNKWALS RGKRELRMSS

SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RVKRYRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGYGRRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL

SEQ ID NO: 2 (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

SEQ ID NO: 3 - PAMP-Gly (aa 22-42 of pre-proADM SEQ ID NO: 1)

ARLDVASEFR KKWNKWALSR G

SEQ ID NO: 4 - MR-proADM (aa 45-92 of pre-proADM SEQ ID NO: 1)

ELRMSSSYPT GLADVKAGPA QTLIRPQDMK GASRSPEDSS PDAARIRV

SEQ ID NO: 5 - CT-proADM (aa 148-185 of pre-proADM SEQ ID NO: 1)

RRRRRSLPEA GPGRTLVSSK PQAHGAPAPP SGSAPHFL

SEQ ID NO: 6 - ADM-Gly 1-53 (aa 95-147 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ GYG

SEQ ID NO: 7 - ADM 1-52 (aa 95-146 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ GY

SEQ ID NO: 8 - ADM fragment 1-51 (aa 95-145 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ G

SEQ ID NO: 9 - ADM fragment 1-50 (aa 95-144 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ

SEQ ID NO: 10 - ADM fragment 1-49 (aa 95-143 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISP

SEQ ID NO: 11 - ADM fragment 1-48 (aa 95-142 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKIS

SEQ ID NO: 12 - ADM fragment 1-47 (aa 95-141 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKI

SEQ ID NO: 13 - ADM fragment 1-46 (aa 95-140 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSK

SEQ ID NO: 14 - ADM fragment 1-45 (aa 95-139 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRS

SEQ ID NO: 15 - ADM fragment 1-44 (aa 95-138 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPR

SEQ ID NO: 16 - ADM fragment 1-43 (aa 95-137 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAP

SEQ ID NO: 17 - ADM fragment 1-42 (aa 95-136 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VA

SEQ ID NO: 18 - ADM fragment 1-41 (aa 95-135 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN V

SEQ ID NO: 19 - ADM fragment 1-40 (aa 95-134 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN

SEQ ID NO: 20 - ADM fragment 1-39 (aa 95-133 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKD

SEQ ID NO: 21 - ADM fragment 1-38 (aa 95-132 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDK SEQ ID NO: 22 - ADM fragment 1-37 (aa 95-131 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKD

SEQ ID NO: 23 - ADM fragment 1-36 (aa 95-130 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDK

SEQ ID NO: 24 - ADM fragment 1-35 (aa 95-129 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTD

SEQ ID NO: 25 - ADM fragment 1-34 (aa 95-128 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFT

SEQ ID NO: 26 - ADM fragment 1-33 (aa 95-127 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQF

SEQ ID NO: 27 - ADM fragment 1-32 (aa 95-126 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQ

SEQ ID NO: 28 - ADM fragment 1-31 (aa 95-125 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI Y

SEQ ID NO: 29 - ADM fragment 1-30 (aa 95-124 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI

SEQ ID NO: 30 - ADM fragment 1-29 (aa 95-123 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQ

SEQ ID NO: 31 - ADM fragment 1-28 (aa 95-122 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAH

SEQ ID NO: 32 - ADM fragment 1-27 (aa 95-121 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLA

SEQ ID NO: 33 - ADM fragment 1-26 (aa 95-120 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKL

SEQ ID NO: 34 - ADM fragment 1-25 (aa 95-119 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQK

SEQ ID NO: 35 - ADM fragment 1-24 (aa 95-118 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQ SEQ ID NO: 36 - ADM fragment 1-23 (aa 95- 117 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTV

SEQ ID NO: 37 - ADM fragment 1-22 (aa 95- 116 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CT

SEQ ID NO: 38 - ADM fragment 1-21 (aa 95- 115 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT C

SEQ ID NO: 39 - ADM fragment 1-20 (aa 95- 114 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT

SEQ ID NO: 40 - ADM fragment 1-19 (aa 95- 113 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFG

SEQ ID NO: 41 - ADM fragment 1-18 (aa 95- 112 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRF

SEQ ID NO: 42 - ADM fragment 1-17 (aa 95- 111 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCR

SEQ ID NO: 43 - ADM fragment 1-16 (aa 95- 110 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGC

SEQ ID NO: 44 - ADM fragment 1-15 (aa 95- 109 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFG

SEQ ID NO: 45 - ADM fragment 1-14 (aa 95- 108 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSF

SEQ ID NO: 46 - ADM fragment 1-13 (aa 95- 107 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRS

SEQ ID NO: 47 - ADM fragment 1-12 (aa 95- 106 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LR

SEQ ID NO: 48 - ADM fragment 1-11 (aa 95- 105 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG L

SEQ ID NO: 49 - ADM fragment 1-10 (aa 95- 104 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG SEQ ID NO: 50 - ADM fragment 1-9 (aa 95-103 of pre-proADM SEQ ID NO: 1) YRQSMNNFQ

SEQ ID NO: 51 - ADM fragment 1-8 (aa 95-102 of pre-proADM SEQ ID NO: 1)

YRQSMNNF

SEQ ID NO: 52 - ADM fragment 1-7 (aa 95-101 of pre-proADM SEQ ID NO: 1) YRQSMNN

SEQ ID NO: 53 - ADM fragment 1-6 (aa 95-100 of pre-proADM SEQ ID NO: 1) YRQSMN

SEQ ID NO: 54 (murine ADM 1-19)

YRQSMNQGSRSNGCRFGTC

SEQ ID NO: 55 - CDR1 of NT-ADM AK in heavy chain

GYTFSRYW

SEQ ID NO: 56 - CDR2 of NT-ADM AK in heavy chain

ILPGSGST

SEQ ID NO: 57 - CDR3 of NT-ADM AK in heavy chain

TEGYEYDGFDY

SEQ ID NO: 58 - CDR1 of NT-ADM AK in light chain

QSIVYSNGNTY

SEQUENCE “RVS” (not part of the Sequencing Listing) - CDR2 of NT-ADM AK in light chain:

RVS

SEQ ID NO: 59 - CDR3 of NT-ADM AK in light chain

FQGSHIPYT

SEQ ID NO: 60 (AM-VH-C)

QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNE

KFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSSASTKGP

SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW

TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYA

QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYA

QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYA

QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYA

QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDQATISCRSSQSrVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DWMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVP

DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DWMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVP

DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 68 (Enibarcimab heavy chain) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQ KFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT

LMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK

SEQ ID NO: 69 (Enibarcimab light chain)

DWLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 70 - human DPP3 (amino acid 1-737)

MADTQYILPNDIGVSSLDCREAFRLLSPTERLYAYHLSRAAWYGGLAVLLQTSPEAPYIYALL SRLFRAQDPDQLRQHALAEGLTEEEYQAFLVYAAGVYSNMGNYKSFGDTKFVPNLPKEKLE RVILGSEAAQQHPEEVRGLWQTCGELMFSLEPRLRHLGLGKEGITTYFSGNCTMEDAKLAQD FLDSQNLSAYNTRLFKEVDGEGKPYYEVRLASVLGSEPSLDSEVTSKLKSYEFRGSPFQVTRG

DYAPILQKWEQLEKAKAYAANSHQGQMLAQYIESFTQGSIEAHKRGSRFWIQDKGPIVESYI GFIESYRDPFGSRGEFEGFVAWNKAMSAKFERLVASAEQLLKELPWPPTFEKDKFLTPDFTS LDVLTFAGSGIPAGINIPNYDDLRQTEGFKNVSLGNVLAVAYATQREKLTFLEEDDKDLYILW KGPSFDVQVGLHELLGHGSGKLFVQDEKGAFNFDQETVINPETGEQIQSWYRSGETWDSKFS

TIASSYEECRAESVGLYLCLHPQVLEIFGFEGADAEDVIYVNWLNMVRAGLLALEFYTPEAFN WRQAHMQARFVILRVLLEAGEGLVTITPTTGSDGRPDARVRLDRSKIRSVGKPALERFLRRLQ VLKSTGDVAGGRALYEGYATVTDAPPECFLTLRDTVLLRKESRKLIVQPNTRLEGSDVQLLE YEASAAGLIRSFSERFPEDGPELEEILTQLATADARFWKGPSEAPSGQA

SEQ ID NO: 71 - human DPP3 (amino acid 474-493 (N-Cys)) - immunization peptide with additional N-terminal Cystein

CETVINPETGEQIQSWYRSGE

SEQ ID NO: 72 - human DPP3 aa 477-482 - epitope of AK1967

INPETG

SEQ ID NO: 73 - human DPP3 aa 480-483

ETGE SEQ ID NO: 74 - variable region of murine AK1967 in heavy chain

QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMSVGWIRQPSGKGLEWLAHIWWNDNKSYNP ALKSRLTISRDTSNNQVFLKIASWTADTGTYFCARNYSYDYWGQGTTLTVSS

SEQ ID NO: 75 - variable region of murine AK1967 in light chain

DVWTQTPLSLSVSLGDPASISCRSSRSLVHSIGSTYLHWYLQKPGQSPKLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK

SEQ ID NO: 76 - CDR1 of murine AK1967 in heavy chain GFSLSTSGMS

SEQ ID NO: 77 - CDR2 of murine AK1967 in heavy chain IWWNDNK

SEQ ID NO: 78 - CDR 3 of murine AK1967 in heavy chain ARNYSYDY

SEQ ID NO: 79 - CDR1 of murine AK1967 in light chain RSLVHSIGSTY

CDR2 of murine AK1967 in light chain

KVS

SEQ ID NO: 80 - CDR3 of murine AK1967 in light chain

SQSTHVPWT

SEQ ID NO: 81 - humanized AK1967 (Procizumab) - heavy chain sequence (IgGlK backbone) MDPKGSLSWRILLFLSLAFELSYGQITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQ PPGKALEWLAHIWWNDNKSYNPALKSRLTITRDTSKNQWLTMTNMDPVDTGTYYCARNY SYDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

SEQ ID NO: 82 - humanized AK1967 (Procizumab) - light chain sequence (IgGlK backbone)

METDTLLLWVLLLWVPGSTGDIVMTQTPLSLSVTPGQPASISCKSSRSLVHSIGSTYLYWYLQ

KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT

EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 83 - ADM 1-52-amide (aa 95-146 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ GY-NH₂

SEQ ID NO: 84 - ADM fragment 1-51-amide (aa 95-145 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ G-NH₂

SEQ ID NO: 85 - ADM fragment 1-50-amide (aa 95-144 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ-NH₂

SEQ ID NO: 86 - ADM fragment 1-49-amide (aa 95-143 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISP-NH₂

SEQ ID NO: 87 - ADM fragment 1-48-amide (aa 95-142 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKIS-NH₂

SEQ ID NO: 88 - ADM fragment 1-47-amide (aa 95-141 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKI-NH₂

SEQ ID NO: 89 - ADM fragment 1-46-amide (aa 95-140 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSK-NH₂

SEQ ID NO: 90 - ADM fragment 1-45-amide (aa 95-139 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRS-NH₂

SEQ ID NO: 91 - ADM fragment 1-44-amide (aa 95-138 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPR-NH₂

SEQ ID NO: 92 - ADM fragment 1-43-amide (aa 95-137 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAP-NH₂

SEQ ID NO: 93 - ADM fragment 1-42-amide (aa 95-136 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VA-NH₂

SEQ ID NO: 94 - ADM fragment 1-41-amide (aa 95-135 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN V-NH₂

SEQ ID NO: 95 - ADM fragment 1-40-amide (aa 95-134 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN-NH₂ SEQ ID NO: 96 - ADM fragment 1-39-amide (aa 95-133 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKD-NH₂

SEQ ID NO: 97 - ADM fragment 1-38-amide (aa 95-132 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDK-NH₂

SEQ ID NO: 98 - ADM fragment 1-37-amide (aa 95-131 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKD-NH₂

SEQ ID NO: 99 - ADM fragment 1-36-amide (aa 95-130 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDK-NH₂

SEQ ID NO: 100 - ADM fragment 1-35-amide (aa 95-129 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFTD-NH₂

SEQ ID NO: 101 - ADM fragment 1-34-amide (aa 95-128 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQFT-NH₂

SEQ ID NO: 102 - ADM fragment 1-33-amide (aa 95-127 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQF-NH₂

SEQ ID NO: 103 - ADM fragment 1-32-amide (aa 95-126 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI YQ-NH₂

SEQ ID NO: 104 - ADM fragment 1-31-amide (aa 95-125 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI Y-NH₂

SEQ ID NO: 105 - ADM fragment 1-30-amide (aa 95-124 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQI-NH₂

SEQ ID NO: 106 - ADM fragment 1-29-amide (aa 95-123 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAHQ-NH₂

SEQ ID NO: 107 - ADM fragment 1-28-amide (aa 95-122 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLAH-NH₂

SEQ ID NO: 108 - ADM fragment 1-27-amide (aa 95-121 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKLA-NH₂

SEQ ID NO: 109 - ADM fragment 1-26-amide (aa 95-120 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQKL-NH₂ SEQ ID NO: 110 - ADM fragment 1-25-amide (aa 95-119 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRFGT CTVQK-NH₂

SEQ ID NO: 111 - ADM fragment 1-24-amide (aa 95-118 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTVQ-NH₂

SEQ ID NO: 112 - ADM fragment 1-23-amide (aa 95-117 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CTV-NH₂

SEQ ID NO: 113 - ADM fragment 1-22-amide (aa 95-116 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT CT-NH₂

SEQ ID NO: 114 - ADM fragment 1-21-amide (aa 95-115 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT C-NH₂

SEQ ID NO: 115 - ADM fragment 1-20-amide (aa 95-114 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFGT-NH₂

SEQ ID NO: 116 - ADM fragment 1-19-amide (aa 95-113 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCRFG-NH₂

SEQ ID NO: 117 - ADM fragment 1-18 (aa 95-112 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG LRSFGCRF-NH₂

SEQ ID NO: 118 - ADM fragment 1-17-amide (aa 95-111 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGCR-NH₂

SEQ ID NO: 119 - ADM fragment 1-16-amide (aa 95-110 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFGC-NH₂

SEQ ID NO: 120 - ADM fragment 1-15-amide (aa 95-109 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSFG-NH₂

SEQ ID NO: 121 - ADM fragment 1-14-amide (aa 95-108 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRSF-NH₂

SEQ ID NO: 122 - ADM fragment 1-13-amide (aa 95-107 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LRS-NH₂

SEQ ID NO: 123 - ADM fragment 1-12-amide (aa 95-106 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG LR-NH₂ SEQ ID NO: 124 - ADM fragment 1-11-amide (aa 95-105 of pre-proADM SEQ ID NO: 1)

YRQSMNNFQG L-NH₂

SEQ ID NO: 125 - ADM fragment 1-10-amide (aa 95-104 of pre-proADM SEQ ID NO: 1) YRQSMNNFQG-NH₂

SEQ ID NO: 126 - ADM fragment 1-9-amide (aa 95-103 of pre-proADM SEQ ID NO: 1) YRQSMNNFQ-NH2

SEQ ID NO: 127 - ADM fragment 1-8-amide (aa 95-102 of pre-proADM SEQ ID NO: 1) YRQSMNNF-NH2

SEQ ID NO: 128 - ADM fragment 1-7-amide (aa 95-101 of pre-proADM SEQ ID NO: 1) YRQSMNN-NH₂

SEQ ID NO: 129 - ADM fragment 1-6-amide (aa 95-100 of pre-proADM SEQ ID NO: 1) YRQSMN-NH₂

SEQ ID NO: 130 - N-terminal extended ADM -1-52 (aa 94-146)

RYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY

SEQ ID NO: 131 - N-terminal extended ADM -2-52 (aa 93-146)

KRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY

SEQ ID NO: 132 - N-terminal extended ADM -3-52 (aa 92-146)

VKRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY

SEQ ID NO: 133 - N-terminal extended ADM -4-52 (aa 91-146)

RVKRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY

SEQ ID NO: 134 - N-terminal extended ADM -1-52-amide (aa 94-146)

RYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-NH2

SEQ ID NO: 135 - N-terminal extended ADM -2-52-amide (aa 93-146)

KRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-NH2

SEQ ID NO: 136 - N-terminal extended ADM -3-52-amide (aa 92-146)

VKRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-NH2

SEQ ID NO: 137 - N-terminal extended ADM -4-52-amide (aa 91-146)

RVKRYRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-NH2 SEQ ID NO: 138 - Peptide # 1 for Epitope mapping of AK1967 bio-AFNFDQETVINPETGEQIQSWYRS

SEQ ID NO: 139 - Peptide # 2 for Epitope mapping of AK1967 bio-AFNFDQETVINPETGEQIQ

SEQ ID NO: 140 - Peptide # 3 for Epitope mapping of AK1967 bio-AFNFDQETVINPETGEQI

SEQ ID NO: 141 - Peptide # 4 for Epitope mapping of AK1967 bio-AFNFDQETVINPETGEQ

SEQ ID NO: 142 - Peptide # 5 for Epitope mapping of AK1967 bio-AFNFDQETVINPETGE

SEQ ID NO: 143 - Peptide # 6 for Epitope mapping of AK1967 bio-AFNFDQETVINPETG

SEQ ID NO: 144 - Peptide # 7 for Epitope mapping of AK1967 bio-AFNFDQETVINPET

SEQ ID NO: 145 - Peptide # 8 for Epitope mapping of AK1967 bio-AFNFDQETVINPE

SEQ ID NO: 146 - Peptide # 9 for Epitope mapping of AK1967 bio-AFNFDQETVINP

SEQ ID NO: 147 - Peptide # 10 for Epitope mapping of AK1967 bio-AFNFDQETVIN

SEQ ID NO: 148 - Peptide # 11 for Epitope mapping of AK1967 ETGEQIQSWYK-bio

SEQ ID NO: 149 - Peptide # 12 for Epitope mapping of AK1967 PETGEQIQSWYK-bio

SEQ ID NO: 150 - Peptide # 13 for Epitope mapping of AK1967 NPETGEQIQSWYK-bio

SEQ ID NO: 151 - Peptide # 14 for Epitope mapping of AK1967 INPETGEQIQSWYK-bio SEQ ID NO: 152 - Peptide # 15 for Epitope mapping of AK1967 VINPETGEQIQSWYK-bio

SEQ ID NO: 153 - Peptide # 16 for Epitope mapping of AK1967

TVINPETGEQIQSWYK-bio

SEQ ID NO: 154 - Peptide # 17 for Epitope mapping of AK1967

ETVINPETGEQIQSWYK-bio

SEQ ID NO: 155 - 40E12 HCDR1

GYAFTTF

SEQ ID NO: 156 - 40E12 HCDR2

NTYSRV

SEQ ID NO: 157 - 40E12 HCDR3

GYGGEGGLGF

SEQ ID NO: 158 - 40E12 LCDR1

RSSQSIIDSDGNTYLE

SEQ ID NO: 159 - 40E12 LCDR2

KVSNRFS

SEQ ID NO: 160 - 40E12 LCDR3

FQGSHFPYT

SEQ ID NO: 161 - 40E12 VH

QIQLVQSGPE LRKPGETVKI SCKASGYAFT TFGMSWIKQA PGQGLKWMGW INTYSRVPKY

TDDFKGRFAF SLEISATTAY LLINNLKNGD TATYFCARGY GGEGGLGFSG QGTTLTVSS

SEQ ID NO: 162 - 40E12 VK

DVLMTQTPFS LPVSLGDQAS ISCRSSQSII DSDGNTYLEW YLQKPGQSPK LLIYKVSNRF

SGVPDRFSGS GSGTDFTLRI SRVEAEDLGV YYCFQGSHFP YTFAGGTKLE LK

SEQ ID NO: 163 - 2004hzVH9

QIQLVQSGSE LKKPGASVKV SCKASGYAFT TFGMSWIRQA PGQGLEWMGW INTYSRVPKY

TQGFTGRFVF SLDISVTTAY LQISSLKAED TAVYFCARGY GGEGGLGFSG QGTLVTVSS

SEQ ID NO: 164 - 2004hzVK7

DWMTQSPLS LPVTLGQPAS ISCRSSQSII DSDGNTYLEW YQQRPGQSPR LLIYKVSNRF

SGVPDRFSGS GSGTDFTLKI SRVEAEDFGV YYCFQGSHFP YTFGQGTKLE IK SEQ ID NO: 165 - 2004hzVK9

DVLMTQSPLS LPVTLGQPAS ISCRSSQSII DSDGNTYLEW YQQRPGQSPR LLIYKVSNRF

SGVPDRFSGS GSGTDFTLKI SRVEAEDFGV YYCFQGSHFP YTFAQGTKLE IK

SEQ ID NO: 166 - Human light chain constant region CL

RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

SEQ ID NO: 167 - Human heavy chain constant region CH

ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

SEQ ID NO: 168 - 2004hz00 LC

DVLMTQTPFS LPVSLGDQAS ISCRSSQSII DSDGNTYLEW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLRI SRVEAEDLGV YYCFQGSHFP YTFAGGTKLE LKRTVAAPSV FIFPPSDEQL KSGTASWCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

SEQ ID NO: 169 - 2004hz00 HC

QIQLVQSGPE LRKPGETVKI SCKASGYAFT TFGMSWIKQA PGQGLKWMGW INTYSRVPKY TDDFKGRFAF SLEISATTAY LLINNLKNGD TATYFCARGY GGEGGLGFSG QGTTLTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSWTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVWDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRWSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK

SEQ ID NO: 170 - 2004hz97 LC

DWMTQSPLS LPVTLGQPAS ISCRSSQSII DSDGNTYLEW YQQRPGQSPR LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDFGV YYCFQGSHFP YTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASWCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

SEQ ID NO: 171 - 2004hz97 HC QIQLVQSGSE LKKPGASVKV SCKASGYAFT TFGMSWIRQA PGQGLEWMGW INTYSRVPKY TQGFTGRFVF SLDISVTTAY LQISSLKAED TAVYFCARGY GGEGGLGFSG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSWTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVWDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRWSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK

SEQ ID No. 172 - 2004hz99 LC

DVLMTQSPLS LPVTLGQPAS ISCRSSQSII DSDGNTYLEW YQQRPGQSPR LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDFGV YYCFQGSHFP YTFAQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASWCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

SEQ ID No. 173 -2004hz99 HC

QIQLVQSGSE LKKPGASVKV SCKASGYAFT TFGMSWIRQA PGQGLEWMGW INTYSRVPKY TQGFTGRFVF SLDISVTTAY LQISSLKAED TAVYFCARGY GGEGGLGFSG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSWTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVWDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRWSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK

SEQ ID NO: 174 - 1F12 HCDR1

GYTFTSY

SEQ ID NO: 175 - 1F12 HCDR2

SAYNGN

SEQ ID NO: 176 - 1F12 HCDR3

EGRSGGSFDI

SEQ ID NO: 177 - 1F12 LCDR1

RASQGISSYLA

SEQ ID NO: 178 - 1F12 LCDR2 DASNLET

SEQ ID NO: 179 - 1F12 LCDR3

QQYDNLPLT

SEQ ID NO: 180 - 1F12 -PTMA HCDR2

SAYQGN

SEQ ID NO: 181 - Ab2004.Am01 HCDR3

EGRWGGSFNI

SEQ ID NO: 182 - Ab2004.Am31 HCDR1

GYTFTQY

SEQ ID NO: 183 - Ab2004.Am31 LCDR1

RASEGISEYLA

SEQ ID NO: 184 - Ab2004.Am32 LCDR1

RAAEGIGSYLA

SEQ ID NO: 185 - Ab2004.Am33 HCDR2

SPYSGN

SEQ ID NO: 186 - Ab2004.Am34 HCDR1

GYTFTHY

SEQ ID NO: 187 - Ab2004.Am34 LCDR2

DVSILDA

SEQ ID NO: 188 - Ab2004.Am36 LCDR2 DASNVDT

SEQ ID NO: 189 - Ab2004.Am37 HCDR2 SPYTGK

SEQ ID NO: 190 - Ab2004.Am38 LCDR2 DTSDLDT

SEQ ID NO: 191 - Ab2004.Am39 LCDR3 QQYDDLDLT

SEQ ID NO: 192 - Ab2004.Am40 LCDR3

QQYDDLPLS SEQ ID NO: 193 - IF12 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW

ISAYNGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG RSGGSFDIWG QGTMVTVSS

SEQ ID NO: 194 - 1F12 -PTMA VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW

ISAYQGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG RSGGSFDIWG QGTMVTVSS

SEQ ID NO: 195 - AB2004.Am01 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW

ISAYQGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG

RWGGSFNIWG QGTMVTVSS

SEQ ID NO: 196 - Ab2004.Am31 VH/ Ab2004.Am32 VH/ Ab2004.Am35 VH/ Ab2004.Am36 VH /

Ab2004.Am40 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT QYGIAWVRQA PGQGLEWMGW

ISAYQGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG

RWGGSFNIWG QGTMVTVSS

SEQ ID NO: 197 - Ab2004.Am33 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW

ISPYSGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG RWGGSFNIWG QGTMVTVSS

SEQ ID NO: 198 - Ab2004.Am34 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT HYGIAWVRQA PGQGLEWMGW

ISAYQGNTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG

RWGGSFNIWG QGTMVTVSS

SEQ ID NO: 199 - Ab2004.Am37 VH/ Ab2004.Am38 VH

QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGLEWMGW

ISPYTGKTNY AQKLQGRVTM TRDTSTSTAY MELRSLRSDD TAVYYCAREG RWGGSFNIWG QGTMVTVSS

SEQ ID NO: 200 - 1F12 VL/ 1F12 -PTMA VL/ Ab2004.Am01 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD ASNLETGVPS

RFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK SEQ ID NO: 201 - Ab2004.Am31 VL/ Ab2004.Am33 VL

DIQMTQSPSS LSASVGDRVT ITCRASEGIS EYLAWYQQKP GKAPKLLIYD ASNLETGVPS

RFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK

SEQ ID NO: 202 - Ab2004.Am32 VL

DIQMTQSPSS LSASVGDRVT ITCRAAEGIG SYLAWYQQKP GKAPKLLIYD

ASNLETGVPSRFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK

SEQ ID NO: 203 - Ab2004.Am34 VL/ Ab2004.Am35 VL/ Ab2004.Am37 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD VSILDAGVPS

RFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK

SEQ ID NO: 204 - Ab2004.Am36 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD

ASNVDTGVPSRFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK

SEQ ID NO: 205 - Ab2004.Am38 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD TSDLDTGVPS

RFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDNLPLTFGG GTKVEIK

SEQ ID NO: 206 - Ab2004.Am39 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD

ASNLETGVPSRFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDDLDLTFGG GTKVEIK

SEQ ID NO: 207 - Ab2004.Am40 VL

DIQMTQSPSS LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYD

ASNLETGVPSRFSGSGSGTD FTFTISSLQP EDIATYYCQQ YDDLPLSFGG GTKVEIK

SEQ ID NO: 208 - humanized anti-DPP3 antibody (PCZ) - heavy chain sequence (IgGlK backbone)

QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALEWLAHIWWNDNKSYNP

ALKSRLTITRDTSKNQWLTMTNMDPVDTGTYYCARNYSYDYWGQGTLVTVSSASTKGPSV

FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM

ISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW

LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

KSLSLSPG

SEQ ID NO: 209 - humanized anti-DPP3 antibody (PCZ)- light chain sequence (IgGlK backbone)

DIVMTQTPLSLSVTPGQPASISCKSSRSLVHSIGSTYLYWYLQKPGQSPQLLIYKVSNRFSGVPD

RFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQ

LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 210 - humanized anti-DPP3 antibody - heavy chain N-terminal signal peptide sequence

MDPKGSLSWRILLFLSLAFELSYG

SEQ ID NO: 211 - humanized anti-DPP3 antibody - light chain N-terminal signal peptide sequence

METDTLLLWVLLLWVPGSTG

SEQ ID NO: 212 - humanized anti-DPP3 antibody (PCZ) - heavy chain sequence (IgGlk backbone) after treatment with Papain (Fab fragment)

QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMSVGWIRQPPGKALEWLAHIWWNDNKSYNP

ALKSRLTITRDTSKNQVVLTMTNMDPVDTGTYYCARNYSYDYWGQGTLVTVSSASTKGPSVF

PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

Claims

Claims

1. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, wherein the fragments have a length of at least 6 amino acids counted from the N-terminus of ADM-Gly and wherein said fragments optionally have a C-terminal amide-group, wherein the level of Dipeptidylpeptidase 3 (DPP3) in a sample of a bodily fluid of said patient is above a threshold.

2. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to claim 1, wherein said ADM-Gly is administered to said patient at a dosage of 1-1000 pg/kg, preferably 5-750 pg/kg, more preferably 10-500 pg/kg, more preferably 15-400 pg/kg, more preferably 20-250 pg/kg, most preferred 25-100 pg/kg.

3. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to claim 1 or 2, wherein said fragments of ADM-Gly (SEQ ID NO: 6) are selected from the group comprising SEQ ID NO: 7 to 53 and SEQ ID NO: 83 to 129.

4. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof according to any one of claims 1 to 3, wherein said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof is modified a) by being covalently bound to another moiety, wherein said moiety is selected from one or more from the group comprising (i) an extension by one or more amino acids, (ii) a protein such as Albumin, e.g. serum Albumin or recombinant serum Albumin, or the Fc region of an IgG, or Transferrin, and (iii) a natural or synthetic polymer, wherein said natural or synthetic polymer is selected from the group comprising HAP, ELP, a carbohydrate, a polysaccharide, PAS, PSA, GLK, XTEN and PEG, preferably ELP, more preferably a carbohydrate, more preferably a polysaccharide, more preferably PAS, more preferably PSA, more preferably GLK, more preferably XTEN and most preferably PEG, or b) via non-covalent binding to serum Albumin, or c) by amino acid manipulation via site directed mutagenesis, including the insertion, deletion or alteration of one or more amino acids within said Adrenomedullin-Gly (SEQ ID NO: 6) or a fragment thereof.

5. A DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

6. An anti-ADM antibody for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with a DPP3 binder, wherein said patient has a level of DPP3 in a sample of bodily fluid above a threshold.

7. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claim 5 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claim 6, wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal part (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 38).

8. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claim 5 or 7 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claim 6 or 7, wherein said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal moiety (comprising amino acid 1) of ADM.

9. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 8 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 8, wherein said antibody or fragment is a monoclonal antibody or fragment that binds to ADM, wherein the heavy chain comprises the sequences:

CDR1 (SEQ ID NO: 55):

GYTFSRYW

CDR2 (SEQ ID NO: 56):

ILPGSGST CDR3 (SEQ ID NO: 57):

TEGYEYDGFDY and wherein the light chain comprises the sequences:

CDR1 (SEQ ID NO: 58):

QSIVYSNGNTY

CDR2: RVS

CDR3 (SEQ ID NO: 59):

FQGSHIPYT; or wherein the heavy chain comprises the following CDR sequences:

CDR1 (SEQ ID No: 155): GYAFTTF,

CDR2 (SEQ ID No: 156): NTYSRV and/ or

CDR3 (SEQ ID No: 157): GYGGEGGLGF and wherein the light chain comprises the following CDR sequences:

CDR1 (SEQ ID No: 158): RSSQSIIDSDGNTYLE,

CDR2 (SEQ ID No: 159): KVSNRFS and/or

CDR3 (SEQ ID No: 160): FQGSHFPYT; or wherein the heavy chain comprises the following CDR sequences:

(i) GYTFTXi Y, where Xi is selected from amino acids S, Q or H,

(ii) SX2 YX3 GX4, where X2 is selected from amino acids from A or P, X3 is selected from amino acids N, Q, S or T and X4 is selected from amino acids N or K

(iii) EGRX5 GGSFXe I, where X5 is selected from amino acids S or W, Xe is selected from amino acids D or N, and wherein light chain comprises the following CDR sequences:

(i) RAX7 Xs GIX9 X10 YLA, where X7 is selected from amino acids S or A, Xs is selected from amino acids Q or E, X9 is selected from amino acids S or G, Xw is selected from amino acids S or E, a. DXn SX12 X13 X14 X15, where Xu is selected from amino acids A, V or T, X12 is selected from amino acids N, I or D, X13 is selected from amino acids L or V, X14 is selected from amino acids E or D, X15 is selected from amino acids T or A,

(ii) QQYDXie LX17 LXis, where Xie is selected from amino acids N or D, X17 is selected from amino acids P or D, Xis is selected from amino acids T or S.

0. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti -ADM antibody or anti -ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 9 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 9, wherein said anti-ADM antibody or anti-ADM antibody fragment comprises a sequence selected from the group comprising the following sequences as a VH region:

SEQ ID NO: 60 (AM-VH-C)

QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGST NYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 61 (AM-VH1)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSG STNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 62 (AM-VH2-E40)

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSG STNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 63 (AM-VH3-T26-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGS TNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK

SEQ ID NO: 64 (AM-VH4-T26-E40-E55)

QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGS TNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK or a sequence that is > 95% identical to it, and comprises a sequence selected from the group comprising the following sequences as a VL region:

SEQ ID NO: 65 (AM-VL-C)

DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNR FSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 66 (AM-VL1)

DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNR DSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 67 (AM-VL2-E40)

DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNR DSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it.

11. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti -ADM antibody or anti -ADM antibody fragment or anti -ADM non-Ig scaffold according to claims 5 or 7 to 10 or anti -ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 10, wherein said anti -ADM antibody or anti-ADM antibody fragment comprises the following sequence as a heavy chain:

SEQ ID NO: 68

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGS TNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a sequence that is > 95% identical to it, and comprises the following sequence as a light chain:

SEQ ID NO: 69 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRF SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a sequence that is > 95% identical to it.

12. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti -ADM antibody or anti -ADM antibody fragment or anti -ADM non-Ig scaffold according to claims 5 or 7 to 11 or anti -ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 11, wherein said DPP3 binder is selected from the group comprising small molecules, anti-DPP3 antibodies, anti-DPP3 antibody fragments and anti-DPP3 non-Ig scaffolds.

13. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti -ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 12 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 12, wherein said DPP3 binder is an anti-DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 70 (full-length DPP3).

14. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 13 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 13, wherein said DPP3 binder is an anti- DPP3 antibody or anti-DPP3 antibody fragment or anti-DPP3 non-Ig scaffold that binds an epitope of at least 4, preferably at least 5, amino acids in length comprised in SEQ ID NO: 71.

15. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 14 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 14, wherein the complementarity determining regions (CDRs) in the heavy chain of said anti-DPP3 antibody or anti-DPP3 antibody fragment comprise the sequences:

SEQ ID NO: 76, SEQ ID NO: 77 and/ or SEQ ID NO: 78 and the CDRs in the light chain comprise the sequences:

SEQ ID NO: 79, KVS and/or SEQ ID NO: 80.

16. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 15 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 15, wherein the heavy chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 81 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 82 or a sequence that is > 95% identical to it.

17. DPP3 binder for use in the treatment of a disease or medical condition in a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to claims 5 or 7 to 15 or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to claims 6 to 15, wherein the heavy chain of said anti- DPP3 antibody comprises the sequence:

SEQ ID NO: 208 or a sequence that is > 95% identical to it and wherein the light chain of said anti-DPP3 antibody comprises the sequence:

SEQ ID NO: 209 or a sequence that is > 95% identical to it.

18. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, or DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to any of the preceding claims, wherein said level of DPP3 is the DPP3 concentration and/or the enzymatic activity of DPP3, wherein particularly said threshold of the DPP3 concentration is between 20 and 120 ng/mL, more preferred between 25 and 80 ng/mL, even more preferred between 30 and 60 ng/mL, most preferred said threshold is 40 ng/mL, or said threshold of enzymatic activity of DPP3 is between 50 and 250 U/L, more preferred between 60 and 225 U/L, even more preferred between 90 and 200 U/L, most preferred said threshold is 185 U/L.

19. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, or DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to any of the preceding claims, wherein said bodily fluid is selected from the group comprising whole blood, serum and plasma.

20. Adrenomedullin-Gly (SEQ ID NO: 6) or fragments or derivatives or modifications thereof for use in the treatment of a disease or medical condition in a patient in need thereof, or DPP3 binder for use in the treatment of a patient in need thereof that is to be treated or has received treatment with an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold or anti-ADM antibody for use in the treatment of a patient in need thereof that is to be treated or has received treatment with a DPP3 binder according to any of the preceding claims, wherein said patient is (i) a patient suffering from severe infection, sepsis, heart failure, chronic heart failure, acute heart failure, myocardial infarction, stroke, (ii) a patient with organ dysfunction or organ failure (e.g. dysfunction or failure of liver, kidney, lung), (iii) a patient undergoing major surgery, (iv) a patient with trauma (e.g. bum trauma, polytrauma), (v) a patient with shock and/ or a patient running into shock, or (vi) a patient with cancer optionally receiving an anti-cancer therapy.