Anti-ADM-antibodies binding to the free N-terminus for accelerated transition of ADM-Gly to bio-ADM in patients with ADM-Gly/ bio-ADM ratio above a threshold and combination with vitamin C

1 . A method of treatment comprising:

treating a patient that is critically ill and suffering from an acute disease or condition selected from the group consisting of: severe infections, shock, acute heart failure, myocardial infarction, stroke, and organ dysfunction by administering an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold to said patient,

wherein said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is administered in an amount sufficient to result in accelerating conversion of ADM-Gly to ADM-NH 2 of circulating ADM-Gly in said patient,

wherein said patient has a ratio of pro-Adrenomedullin or a fragment thereof to ADM-NH 2 (SEQ ID No. 20) above a predetermined threshold in a sample of bodily fluid taken from said patient prior to administration of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold,

wherein said pro-Adrenomedullin or fragment thereof is selected from the group consisting of PAMP (SEQ ID No. 32), MR-proADM (SEQ ID No. 33), ADM-Gly (SEQ ID No. 21) and CT-proADM (SEQ ID No. 34), and

wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal and/or mid-regional part (aa 1-42) of ADM-Gly and/or ADM-NH 2 : YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA (SEQ ID No. 23), and

wherein the heavy chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 1

GYTFSRYW,

SEQ ID No.: 2

ILPGSGST, and

SEQ ID No.: 3

TEGYEYDGFDY

and wherein the light chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 4

QSIVYSNGNTY,

SEQUENCE: RVS, and

SEQ ID No.: 5

FQGSHIPYT.

2 . The method according to claim 1 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-Gly and/or ADM-NH 2 : YRQSMNNFQGLRSFGCRFGTC (SEQ ID No. 14).

3 . The method according to claim 1 wherein said anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminal end (amino acid 1) of ADM-Gly and/or ADM-NH 2 .

4 . The method according to claim 1 wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the mid-regional part (amino acids 21-42) of ADM-Gly and/or ADM-NH 2 : CTVQKLAHQIYQFTDKDKDNVA (SEQ ID No. 48).

5 . The method according to claim 4 wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the mid-regional part (amino acids 21-32) of ADM-Gly and/or ADM-NH 2 : CTVQKLAHQIYQ (SEQ ID No.: 15).

6 . The method according to claim 1 wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the mid-regional part (amino acids 21-42) of ADM-Gly and/or ADM-NH 2 : CTVQKLAHQIYQFTDKDKDNVA (SEQ ID No. 48).

7 . The method according to claim 6 wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the mid-regional part (amino acids 21-32) of ADM-Gly and/or ADM-NH 2 : CTVQKLAHQIYQ (SEQ ID No.: 15).

8 . The method according to claim 6 wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the mid-regional part (amino acids 27-39) of ADM-Gly and/or ADM-NH 2 : AHQIYQFTDKDKD (SEQ ID No.: 49).

9 . The method according to claim 1 wherein the sample additionally comprises a predetermined level of pro-Adrenomedullin or a fragment thereof consisting of the group of PAMP (SEQ ID No. 32), MR-proADM (SEQ ID No. 33), ADM-Gly (SEQ ID No. 21) CT-proADM (SEQ ID No. 34) and ADM-NH 2 (SEQ ID No. 20).

10 . The method according to claim 1 wherein the ADM-Gly/ADM-NH 2 ratio in said sample is above 1.

11 . The method of claim 10 wherein the ADM-Gly/ADM-NH 2 ratio is above 1.5.

12 . The method of claim 10 wherein the ADM-Gly/ADM-NH 2 ratio is above 2.5.

13 . The method according to claim 1 wherein the sample of bodily fluid of said patient is selected from the group of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva.

14 . The method according to claim 13 wherein said sample is selected from the group comprising human citrate plasma, heparin plasma and EDTA plasma.

15 . The method according to claim 1 additionally requiring measuring the ratio of pro-Adrenomedullin or a fragment thereof and ADM-NH 2 with an immunoassay, and wherein said pro-Adrenomedullin or fragment thereof is selected from the group consisting of PAMP (SEQ ID No. 32), MR-proADM (SEQ ID No. 33), ADM-Gly (SEQ ID No. 21) and CT-proADM (SEQ ID No. 34).

16 . The method according to claim 15 wherein said immunoassay is a sandwich immunoassay.

17 . The method of claim 16 wherein said immunoassay is a fully automated assay.

18 . The method according to claim 1 wherein the immunoassay sensitivity of said assay for the detection of ADM-NH 2 is able to quantify ADM-NH 2 of healthy subjects and is <70 pg/ml.

19 . The method of claim 18 wherein the assay sensitivity of said assay for the detection of ADM-NH 2 is <40 pg/ml.

20 . The method of claim 18 wherein the assay sensitivity of said assay for the detection of ADM-NH 2 is <10 pg/ml.

21 . The method according to claim 1 wherein the immunoassay sensitivity for ADM-Gly is 20 pg/ml.

22 . The method of claim 21 wherein the assay sensitivity of said assay for ADM-Gly is 15 pg/ml.

23 . The method of claim 21 wherein the assay sensitivity of said assay for ADM-Gly is 10 pg/ml.

24 . The method according to claim 1 wherein the level of pro-Adrenomedullin or a fragment thereof and ADM-NH 2 (SEQ ID No. 20) is determined by using one binder to said pro-Adrenomedullin or a fragment thereof and a second binder to ADM-NH 2 (SEQ ID No. 20), and

wherein said proAdrenomedullin or a fragment thereof is selected from the group consisting of PAMP (SEQ ID No. 32), MR-proADM (SEQ ID No. 33), ADM-Gly (SEQ ID No. 21) and CT-proADM (SEQ ID No. 34).

25 . The method of claim 1 wherein said severe infection is selected from the group consisting of meningitis, systemic inflammatory response syndrome (SIRS), and sepsis.

26 . The method of claim 1 wherein said shock is septic shock or cardiogenic shock.

27 . The method of claim 1 wherein said acute heart failure is acute decompensated heart failure, or chronic heart failure with worsening signs and symptoms.

28 . The method of claim 1 wherein said organ dysfunction is kidney dysfunction, liver dysfunction, heart dysfunction, or lung dysfunction.

29 . A method for the therapy of a patient, comprising:

administering to said patient an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold,

wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal and/or mid-regional part (amino acids 1-42) of ADM-Gly and/or ADM-NH 2 :

YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA (SEQ ID No. 23),

wherein the heavy chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 1

GYTFSRYW,

SEQ ID No.: 2

ILPGSGST, and

SEQ ID No.: 3

TEGYEYDGFDY

and wherein the light chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 4

QSIVYSNGNTY,

SEQUENCE: RVS, and

SEQ ID No.: 5

FQGSHIPYT

wherein a level of peptidylglycine alpha-amidating monooxygenase (PAM) and/or its isoforms and/or fragments thereof is below a predetermined threshold in a sample of bodily fluid taken from said patient before administering an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and

wherein said patient is suffering from an acute disease or condition selected from the group consisting of: severe infections, shock, acute heart failure, myocardial infarction, stroke, and organ dysfunction.

30 . The method according to claim 29 , wherein said level of PAM and/or its isoforms and/or fragments thereof is the total concentration of PAM and/or its isoforms and/or fragments thereof having at least 12 amino acids or the activity of PAM and/or its isoforms and/or fragments thereof comprising the sequences SEQ ID No. 39, SEQ ID No. 40, SEQ ID No. 41, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 44, SEQ ID No. 45, SEQ ID No. 46 and SEQ ID No. 47.

31 . A method comprising:

administering to said patient an anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold in combination with L-ascorbic acid,

wherein the heavy chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 1

GYTFSRYW,

SEQ ID No.: 2

ILPGSGST, and

SEQ ID No.: 3

TEGYEYDGFDY

and wherein the light chain of said anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold comprises:

SEQ ID No.: 4

QSIVYSNGNTY,

SEQUENCE: RVS, and

SEQ ID No.: 5

FQGSHIPYT;

wherein said patient is suffering from an acute disease or condition selected from the group consisting of: severe infections, shock, acute heart failure, myocardial infarction, stroke, and organ dysfunction, and

wherein at least one of a, b, c, d, or e is satisfied:

a. stabilizing the systemic circulation of said patient who is suffering from an acute disease or acute condition, wherein said patient is in need of stabilizing the systemic circulation, wherein said patient exhibits a heart rate of >100 beats/min and/or <65 mm Hg mean arterial pressure, and wherein stabilizing the systemic circulation means increasing the mean arterial pressure over 65 mmHg,

b. preventing a heart rate increase to >100 beats/min and/or a mean arterial pressure decrease to <65 mm Hg in patients having an acute disease or acute condition,

c. preventing or reducing organ dysfunction or preventing organ failure in said patient suffering from a chronic and/or acute disease or acute condition, and wherein said organ is selected from the group consisting of heart, kidney, liver, lungs, pancreas, small intestines and spleen,

d. achieving therapy or prevention of SIRS, meningitis, sepsis, or shock, in said patient,

e. reducing mortality risk in a patient with SIRS, meningitis, sepsis, or shock;

wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM non-Ig scaffold binds to the N-terminal and/or mid-regional part (amino acids 1-42) of ADM-Gly and/or ADM-NH 2 : YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA (SEQ ID No. 23);

and optionally wherein said L-ascorbic acid is a single enantiomer, a mixture of enantiomers, a mixture of diastereomers or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and

wherein said patient has a ratio of pro-adrenomedullin or a fragment thereof to ADM-NH 2 (SEQ ID No. 20) above a predetermined threshold in a sample of bodily fluid taken from the patient prior to administration of the anti-Adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold in combination with L-ascorbic acid.