Anti-gastrin antibodies and uses thereof

Abstract

The present invention provides for monoclonal antibodies binding to sulfated and non-sulfated amidated gastrin 17. Further, the present invention provides for kits and compositions comprising such antibodies and diagnostic uses and methods employing such antibodies, compositions, and / or kits. Furthermore, herein provided are, inter alia, nucleic acids encoding such antibodies, host cells comprising the same, as well as means and methods for the production of such antibodies.

Description

[0001] Anti-gastrin antibodies and uses thereof

[0002] The present invention provides for monoclonal antibodies binding to sulfated and non-sulfated amidated gastrin 17. Further, the present invention provides for kits and compositions comprising such antibodies and diagnostic uses and methods employing such antibodies, compositions, and / or kits. Furthermore, herein provided are, inter alia, nucleic acids encoding such antibodies, host cells comprising the same, as well as means and methods for the production of such antibodies.

[0003] Gastrins are a group of peptide hormones primarily produced by antral G cells and endocrine cells of the antral gastric glands with diverse local functions in the gastrointestinal system, including inducing the release of gastric acid into the stomach and the stimulation of the growth and maintenance of the gastric epithelium [Rehfeld (2012) Clin Chem 58(5), 831-6], Furthermore, gastrins are secreted into the blood stream resulting in their systemic distribution [Rehfeld 2012, loc. cit . Gastrins are secreted in response to various stimuli including, inter alia, stimulation of the vagus nerve, distension of the stomach antrum or the presence of soluble amino acids in the stomach [Duan (2021) Function (Oxf). 26;3(1); Richardson (1976) J Clin Invest. 58(3), 623-631.]. Furthermore, reduced levels of gastric acid or the absence of gastric acid secretion into the stomach may also result in increased circulating gastrin concentrations [Rehfeld 2012, loc. cit:, Cesario (2018) Acta Biomed 89(8-s), 33-39],

[0004] Gastrins are produced as preprograstrin (comprising 101 amino acids), cleaved to progastrin (comprising 80 amino acids), and further processed into gastrin 34 (G34; comprising 34 amino acids). G34 may be further N-terminally cleaved into the shorter 17-amino acid gastrin 17 (G17 or gastrin-17) [Fourmy (2011) Gastroenterology 141(3), 814-818], G17 is structurally related to the peptide hormone cholecystokinin (CCK33). Although G17 is the predominant product, G34 is the major circulating form of gastrin due to its slower rate of clearance [Chao & Hellmich (2012) Physiology of the Gastrointestinal Tract Vol. 1, 115-154], G17 and G34 are the most abundant gastrins and may both be post-translationally modified. Such post-translational modifications comprise, inter alia, amidation of the carboxy -terminus (i.e., substitution of the C-terminal glycine residue with an amine group) of G17 or G34. Such amidated forms of G17 and G34 are often considered bioactive gastrins and exert their effects through binding to the cholecystokinin receptor (CCK2R; previously named CCK-B [Fourmy (2011) loc. cit , Dufresne(2006) Physiological reviews 86(3), 805-847], Approx. 95% of bioactive gastrins are amidated gastrins, whereof 85% are amidated G17, 5-10% are amidated G34, while the rest is a mixture of other gastrins. [Rehfeld (2003) Encyclopedia of Hormones and Related Cell Regulators, Gl-8] Further, G17 may comprise several optional posttranslational modifications [Daugherty (1989) Physiol Rev. 69(2), 482-502], These include oxidization of the sidechain of a methionine residue, O- sulfation of a tyrosine sidechain comprised in G17 and formation of a pyroglutamate residue on the N-terminus of G17. Accordingly, amidated G17 may have a variety of different structures, that are exemplified in SEQ IDs NO: 56 to 63, while amidated gastrin 17, as routinely detected in body fluids comprises an N-terminal pyroglutamate residue. Accordingly, bioactive variants of amidated gastrin 17 that are of particular relevance e.g. for diagnostic detection and / or quantification gastrin 17 levels are exemplified in SEQ IDs NO: 56 to 58 and 60.

[0005] Gastrins have been linked to various diseases of the stomach including chronic gastritis, a chronic inflammation of the mucosal tissue of the stomach. Chronic gastritis can occur in the corpus and / or the antrum and can be caused by Heliobacter pylori infections or can arise in the context of gastric autoimmunity [Annibale (2020) Expert Review of Gastroenterology & Hepatology 14:2, 93-102], Chronic gastritis usually emerges as non-atrophic gastritis but may develop into the more severe atrophic gastritis. During the development of atrophic gastritis, gastric mucosal tissues, namely gastric glands, are gradually lost. Atrophic gastritis progresses slowly and may finally result in severe, advanced atrophy, i.e., in total or nearly total loss of normal gastric glands [Agreus (2012) Scand J Gastroenterol 47(2), 136-147; Agreus (2012) Scand J Gastroenterol 47(12), 1525], Hence, atrophic gastritis can affect gastrin production and / or secretion into the blood stream. Furthermore, patients having atrophic gastritis are at an increased risk for the development of gastric cancer (i.e., adenocarcinoma) [Giannakis (2008) Proc Natl Acad Sci U S A 105(11), 4358-4363] or anemia [Annibale (2020) loc. cit.}. Accordingly, early diagnosis of chronic gastritis, in particular atrophic gastritis, is of relevance in the art.

[0006] The diagnosis of atrophic gastritis can be conducted via gastroscopy which is, however, comparably labor intensive. Thus, serological tests (like the quantification of G17 and pepsinogens in blood plasma) are often employed to initially screen and identify patients who subsequently need to undergo gastroscopy [Annibale (2020) loc. cit.}. [Agreus (2012) loc. cit.] and enclosed Figure 1 (as published in Agreus (2012) Scand J Gastroenterol 47(12), 1525) provide for an algorithm that allows the skilled artisan to diagnose non-atrophic gastritis and atrophic gastritis in the corpus and / or the antrum based on immunological detection and / or quantification of G17, H. pylori, and pepsinogen. Immunological detection and / or quantification of G17 using G17-specific antibodies in diagnostic assays has been described before. Here, diagnostic assays often make use of two separate antibodies that bind different epitopes of G17. For example WO 2004 / 4088326 and EP3258266B1 provide for methods employing a first and a second anti -gastrin 17 antibody binding to different epitopes of gastrin 17. Furthermore, several gastrin detection assays (i.e., Biohit and Snibe) are commercially available. However, as will be detailed herein below, come with undesired disadvantages including:

[0007] - High limit of detection (see enclosed Example 11), indicating that low concentrations of G17 may result in false negative results,

[0008] - High limit of blank (see enclosed Example 11), indicating that low concentrations of G17 may result in false positive results,

[0009] - High limit of quantification (see enclosed Example 11), indicating that low concentrations of G17 may not be accurately quantified,

[0010] - High sample volumes (see enclosed Example 10),

[0011] - Reduced detection of posttranslationally modified (sulfated) variants of G17 (see, inter alia, enclosed Example 10).

[0012] Accordingly, there is a need in the art for the provision of improved means and methods for the detection of G17.

[0013] This technical problem is solved by the invention as described herein below and as characterized in the appended claims. This is, inter alia, evident from the illustrative and non-limiting examples clearly demonstrating that the herein provided antibodies effectively bind to G17 with surprisingly advantageous analytical performance and / or specificity. Thus, the present inventors could surprisingly overcome the above caveats of prior art antibodies and / or diagnostic methods. Accordingly, the herein provided antibodies allow for superior detection of G17 in, inter alia, the herein provided diagnostic methods, as compared to state of the art diagnostic assays of Biohit and Snibe.

[0014] As is illustratively shown in the enclosed examples, the herein provided antibodies allow for the specific detection amidated (i.e., bioactive) G17 and, accordingly, do not cross-react with non- amidated G17 or structurally related peptides such as G34 or CCK33. As is further detailed herein below, specifically, the combination of the herein provided antibodies (i.e., the combination of an antibody binding the N-terminus of G17 and an antibody binding the C-terminus of G17) allows for the detection of amidated (i.e., bioactive) G17 and, accordingly, avoids cross-reactivity with non-amidated G17 or structurally related peptides such as G34 or CCK33. Further, the herein provided antibodies allow for superior detection of both sulfated and non-sulfated G17 (e.g., SEQ ID NO: 61 and SEQ ID NO: 63, respectively). This is particularly advantageous in light of the disclosure of Andersen (1984) Scandinavian Journal of Clinical and Laboratory Investigation 44:supl68, 5-24, which teaches that the degree of gastrin sulfation differs with the localization thereof in the digestive tract and between healthy and diseased patients. Further, the said antibodies do not discriminate between G17 comprising an oxidized or a non-oxidized methionine sidechain (e.g., SEQ ID NO: 62 and SEQ ID NO: 63, respectively).

[0015] Hence, the herein provided antibodies allow for the accurate detection of all known bioactive G17 variants.

[0016] Accordingly, the present invention provides for a first monoclonal antibody binding to the C- terminus of C-terminally amidated gastrin 17. The present invention provides in one aspect for a monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence of: YMGWMDF (SEQ ID NO: 96) or YGWMDF (SEQ ID NO: 92), wherein said antigen is comprised in C-terminally amidated gastrin or C-terminally amidated cholecystokinin (CCK33), wherein F in position 7 in SEQ ID NO: 96 or F in position 6 in SEQ ID NO: 92 is C- terminally amidated, wherein the sulfur atom comprised in the sulfide group of M in position 5 in SEQ ID NO: 96 or of M in position 4 in SEQ ID NO: 92 may be oxidized, wherein the side chain of Y in position 1 in SEQ ID NO: 96 or of Y in position 1 in SEQ ID NO: 92 may be O-sulfated. In one aspect, the present invention provides for a monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98.

[0017] It is evident, inter alia, from illustrative and non-limiting Example 6 that said first monoclonal antibody possesses highly advantageous characteristics (e.g., surprisingly high antigen binding affinities) that could not have been expected based on the prior art.

[0018] Furthermore, the present invention provides for a second monoclonal antibody specifically binding to the N-terminus of gastrin 17. Accordingly, the present invention provides in one aspect for a monoclonal antibody specifically binding to gastrin 17 comprising an N-terminal pyroglutamate residue. It is evident, inter alia, from illustrative and non-limiting Example 6 that said second monoclonal antibody possesses highly advantageous characteristics (e.g., surprisingly high antigen binding affinities) that could not have been expected based on the prior art.

[0019] Furthermore, the present invention also provides for an in vitro immunoassay method for the detection and / or for the quantification of gastrin, wherein the method comprises the steps of: a) contacting a sample of a subject with the first monoclonal antibody binding to the C- terminus of C-terminally amidated gastrin 17 and / or the second monoclonal antibody specifically binding to the N-terminus of gastrin 17; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to gastrin.

[0020] As detailed herein above and herein below, the herein provided method possesses highly advantageous characteristics as compared to the state of the art methods provided by Biohit (Biohit Gastrin- 17 ELISA; Cat. No. 601035) and Snibe (Snibe Gastrin- 17 assay; Cat. No. 130201022M).

[0021] The present invention provides for the following items:

[0022] 1. A monoclonal antibody binding to the C-terminus of C-terminally amidated gastrin 17.

[0023] 2. A monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence of: YMGWMDF (SEQ ID NO: 96) or YGWMDF (SEQ ID NO: 92), wherein F in position 7 in SEQ ID NO: 96 or F in position 6 in SEQ ID NO: 92 is C- terminally amidated, wherein the sulfur atom comprised in the sulfide group of M in position 5 in SEQ ID NO: 96 or of M in position 4 in SEQ ID NO: 92 may be oxidized, wherein the side chain of Y in position 1 in SEQ ID NO: 96 or of Y in position 1 in SEQ ID NO: 92 may be O-sulfated. A monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98. A monoclonal antibody specifically binding to an epitope consisting of an amino acid sequence of GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized. The monoclonal antibody according to any one of items 1 to 4, wherein said monoclonal antibody specifically binds to an epitope consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58;

[0024] V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54;

[0025] Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 1 to 7, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90% amino acid sequence identity to SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33. The monoclonal antibody according to any one of items 1 to 7, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15. The monoclonal antibody according to any one of items 1 to 7, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90% amino acid sequence identity to SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, SEQ ID NO: 32, or a variant of SEQ ID NO: 14 or SEQ ID NO: 32 with at least about 90% amino acid sequence identity to SEQ ID NO: 14 or SEQ ID NO: 32, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33. The monoclonal antibody according to any one of items 1 to 7, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with amino acid substitutions in position 1 and / or 4 of SEQ ID NO:

[0026] 14, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO:

[0027] 15. The monoclonal antibody according to any one of items 8 to 11, wherein said monoclonal antibody comprises a VH with W in position 47 of and wherein said position is indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 8 to 12, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 26, or a variant of SEQ ID NO: 6 or SEQ ID NO: 26 with at least about 90% amino acid sequence identity to SEQ ID NO: 6 or SEQ ID NO: 26, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 27, or a variant of SEQ ID NO: 7 or SEQ ID NO: 27 with at least about 90% amino acid sequence identity to SEQ ID NO: 7 or SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 7, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 28, or a variant of SEQ ID NO: 8 or SEQ ID NO: 28 with at least about 90% amino acid sequence identity to SEQ ID NO: 8 or SEQ ID NO: 28, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant of SEQ ID NO: 9 with at least about 90% amino acid sequence identity to SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 34, or a variant of SEQ ID NO: 16 or SEQ ID NO: 34 with at least about 90% amino acid sequence identity to SEQ ID NO: 16 or SEQ ID NO: 34, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 35, or a variant of SEQ ID NO: 17 or SEQ ID NO: 35 with at least about 90% amino acid sequence identity to SEQ ID NO: 17 or SEQ ID NO: 35, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant of SEQ ID NO: 18 with at least about 90% amino acid sequence identity to SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant of SEQ ID NO: 19 with at least about 90% amino acid sequence identity to SEQ ID NO: 19. The monoclonal antibody according to any one of items 8 to 12, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with amino acid substitutions in one or more positions selected from positions 5, 15, 19, 21, and 24 of SEQ ID NO: 6, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with an amino acid substitution in position 8 of SEQ ID NO: 7, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with amino acid substitutions in position 10 and / or 13 of SEQ ID NO: 8 and comprising a deletion in position 9 of SEQ ID NO: 8, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with an amino acid substitution in position 16 of SEQ ID NO: 16, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with amino acid substitutions in position 2 and / or 6 of SEQ ID NO: 17, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. The monoclonal antibody according to any one of items 1 to 14, wherein said monoclonal antibody comprises: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 according to any one of items 8 to ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 according to item 13 or 14; and b) a VL comprising or consisting of: i. the CDR-L1, the CDR-L2, and the CDR-L3 according to any one of items 8 to 11, and ii. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 according to item 13 or 14. The monoclonal antibody according to any one of items 1 to 15, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 15, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 17, wherein said monoclonal antibody comprises or consists of a Fragment Antigen Binding region (Fab region) and wherein said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i. the VH according to item 15, and 11. the CHI according to item 16 or 17; and b) a light chain comprising or consisting of: i. the VL according to item 15, and ii. the CL according to item 16 or 17.

[0028] 19. The monoclonal antibody according to any one of items 1 to 18, wherein said monoclonal antibody does not bind to C-terminally non-amidated gastrin.

[0029] 20. The monoclonal antibody according to any one of items 1 to 19, wherein said monoclonal antibody comprises an association rate constant (ka) of about or at least about 1.21 x 106M^s'1to when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5.

[0030] 21. The monoclonal antibody according to any one of items 1 to 20, wherein said monoclonal antibody comprises a dissociation rate constant kd of about or less than about 5.05 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5.

[0031] 22. The monoclonal antibody according to any one of items 1 to 21, wherein said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 4.17 x IO'10M when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5.

[0032] 23. The monoclonal antibody according to any one of items 1 to 22, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the KD differs by about or less than about 25%.

[0033] 24. The monoclonal antibody according to any one of items 1 to 23, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 72%. 25. The monoclonal antibody according to any one of items 1 to 24, wherein said monoclonal antibody is a Fab fragment.

[0034] 26. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58;

[0035] V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0036] 27. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54;

[0037] Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0038] 28. The monoclonal antibody according to any one of items 1 to 5, 26, and 27, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0039] 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0040] 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 13, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 15. The monoclonal antibody according to any one of items 1 to 5, 26, and 27, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15. The monoclonal antibody according to any one of items 1 to 5, 26, and 27, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0041] 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0042] 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0043] 13, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0044] 14, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0045] 15,

[0046] 31. The monoclonal antibody according to any one of items 1 to 5, 26, and 26, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

[0047] 32. The monoclonal antibody according to any one of items 28 to 31, wherein said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 28 to 32, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 6, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 7, preferably a variant with W in position 8 of SEQ ID NO: 7, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 8, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 16, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 17, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 19. The monoclonal antibody according to any one of items 28 to 32, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C-terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C-terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. The monoclonal antibody according to any one of items 1 to 5, and 26 to 34, wherein said monoclonal antibody comprises: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 according to any one of items 28 to 31, and ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 according to item 33 or 34; and b) a VL comprising or consisting of: i. the CDR-L1, the CDR-L2, and the CDR-L3 according to any one of items 28 to 31, and ii. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 according to item 33 or 34. The monoclonal antibody according to any one of items 1 to 5, and 26 to 35, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 5, and 26 to 35, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 5, and 26 to 37, wherein said monoclonal antibody comprises or consists of a Fab region and wherein said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i. the VH according to item 35, and ii. the CHI according to item 36 or 37; and b) a light chain comprising or consisting of: i. the VL according to item 35, and ii. the CL according to item 36 or 37. The monoclonal antibody according to any one of items 1 to 5, and 26 to 38, wherein said monoclonal antibody does not bind to C-terminally non-amidated gastrin. The monoclonal antibody according to any one of items 1 to 5, and 26 to 39, wherein said monoclonal antibody comprises an association rate constant (ka) of about or at least about 1.89 x 106M^s'1± about 0.03 x 106M^s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 26 to 39, wherein said monoclonal antibody comprises an dissociation rate constant kd of about or less than about 1.90 x 10'4s'1± about 0.01 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 26 to 41, wherein said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 9.60 x 10'11M ± about 0.1 x 10'11M when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 26 to 42, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the KD differs by about or less than about 16%. The monoclonal antibody according to any one of items 1 to 5, and 26 to 43, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 41%. The monoclonal antibody according to any one of items 1 to 5, and 26 to 44, wherein said monoclonal antibody is a Fab fragment. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58;

[0048] V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; W in position 32; Y in position 91; D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 1 to 5, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54;

[0049] Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 1 to 5, 46, and 47, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0050] 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0051] 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 31, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 33. The monoclonal antibody according to any one of items 1 to 5, 46, and 47, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33. The monoclonal antibody according to any one of items 1 to 5, 46, and 47, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0052] 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0053] 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0054] 31, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0055] 32, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0056] 33, The monoclonal antibody according to any one of items 1 to 5, 46, and 47, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33. The monoclonal antibody according to any one of items 48 to 51, wherein said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 48 to 52, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 26, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 27, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 28, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 34, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 35, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 19. The monoclonal antibody according to any one of items 48 to 52, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. The monoclonal antibody according to any one of items 1 to 5, and 46 to 54, wherein said monoclonal antibody comprises: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 according to any one of items 48 to 51, and ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 according to item 53 or 54; and b) a VL comprising or consisting of: i. the CDR-L1, the CDR-L2, and the CDR-L3 according to any one of items 48 to 51, and ii. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 according to item 53 or 54. The monoclonal antibody according to any one of items 1 to 5, and 46 to 55, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 5, and 46 to 55, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20. The monoclonal antibody according to any one of items 1 to 5, and 46 to 57, wherein said monoclonal antibody comprises or consists of a Fab region and wherein said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i. the VH according to item 55, and ii. the CHI according to item 56 or 57; and b) a light chain comprising or consisting of: i. the VL according to item 55, and ii. the CL according to item 56 or 57. The monoclonal antibody according to any one of items 1 to 5, and 46 to 58, wherein said monoclonal antibody does not bind to C-terminally non-amidated gastrin. The monoclonal antibody according to any one of items 1 to 5, and 46 to 59, wherein said monoclonal antibody comprises an association rate constant (ka) of about or at least about 1.21 x 106M^s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 46 to 60, wherein said monoclonal antibody comprises an dissociation rate constant kd of about or less than about 5.05 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 46 to 61, wherein said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 4.17 x IO'10M when contacted with a polypeptide comprising or consisting of the epitope according to item 4 or 5. The monoclonal antibody according to any one of items 1 to 5, and 46 to 62, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the KD differs by about or less than about 25%. The monoclonal antibody according to any one of items 1 to 5, and 46 to 63, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 72%. The monoclonal antibody according to any one of items 1 to 5, and 46 to 64, wherein said monoclonal antibody is a Fab fragment. A monoclonal antibody specifically binding to gastrin 17 comprising an N-terminal pyroglutamate residue. The monoclonal antibody according to item 66, wherein said monoclonal antibody specifically binds to an epitope consisting of an amino acid sequence of: XGPWLEE (SEQ ID NO: 99), wherein X in position 1 in SEQ ID NO: 99 is a pyroglutamate residue. The monoclonal antibody according to item 66 or 67, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; W in position 58; D in position 95; Y in position 96; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. The monoclonal antibody according to item 66 or 67, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; I in position 52A; R in position 53; W in position 58; D in position 95; Y in position 96; A in position 97; G in position 98; G in position 99; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; A in position 92; T in position 93; Y in position 94; T in position 95; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0057] 70. The monoclonal antibody according to any one of items 66 to 69, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0058] 39, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0059] 40, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0060] 41, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 48, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 50.

[0061] 71. The monoclonal antibody according to any one of items 66 to 69, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50.

[0062] 72. The monoclonal antibody according to any one of items 66 to 69, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0063] 39, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0064] 40, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0065] 41, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0066] 48, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0067] 49, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO:

[0068] 50,

[0069] 73. The monoclonal antibody according to any one of items 66 to 69, wherein said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, v. a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49, and vi. a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50. The monoclonal antibody according to any one of items 70 to 73, wherein said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme. The monoclonal antibody according to any one of items 70 to 73, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 42, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 43, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 44 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 4, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 51, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 52, vii. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 53, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 19. The monoclonal antibody according to any one of items 70 to 73, wherein said monoclonal antibody further comprises: i. a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42, ii. a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43, iii. a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C- terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 43, iv. a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, v. a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51, vi. a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52, vn. a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C- terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53, and viii. a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. The monoclonal antibody according to any one of items 66 to 76, wherein said monoclonal antibody comprises: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 according to any one of items 70 to 73, and ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 according to item 75 or 76; and b) a VL comprising or consisting of: i. the CDR-L1, the CDR-L2, and the CDR-L3 according to any one of items 70 to 73, and ii. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 according to item 75 or 76. The monoclonal antibody according to any one of items 66 to 77, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 54. The monoclonal antibody according to any one of items 66 to 77, wherein said monoclonal antibody further comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54. The monoclonal antibody according to any one of items 66 to 79, wherein said monoclonal antibody comprises or consists of a Fab region and wherein said Fab region comprises or consists of: : a) a Fab region heavy chain comprising or consisting of: i. the VH according to item 77, and ii. the CHI according to item 78 or 79; and b) a light chain comprising or consisting of: i. the VL according to item 77, and ii. the CL according to item 78 or 79. The monoclonal antibody according to any one of items 66 to 80, wherein said monoclonal antibody comprises an association rate constant (ka) of about or at least about 4.17 x 106M^s'1± about 0.05 x 106M^s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 70. The monoclonal antibody according to any one of items 66 to 81 , wherein said monoclonal antibody comprises an dissociation rate constant kd of about or less than about 1.29 x 10’4s'1± about 0.01 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope according to item 70. The monoclonal antibody according to any one of items 66 to 82, wherein said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 3.09 x 10'11M ± about 0.05 x 10'11M when contacted with a polypeptide comprising or consisting of the epitope according to item 70. The monoclonal antibody according to any one of items 66 to 83, wherein said monoclonal antibody does not bind to CCK33. The monoclonal antibody according to any one of items 66 to 84, wherein said monoclonal antibody does not bind to gastrin 34. The monoclonal antibody according to any one of items 66 to 85, wherein said monoclonal antibody is a Fab fragment. A multivalent antibody comprising or consisting of the monoclonal antibody to any one of items 1 to 65, and the monoclonal antibody according to any one of items 66 to 86. A nucleic acid molecule comprising a nucleic acid sequence encoding one or more selected from the group consisting of the following: a) the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of items 66 to 86; b) the multivalent antibody according to item 87; c) an antigen-binding fragment according to a) and / or b); and d) a polypeptide comprising a), b), and / or c). A nucleic acid vector comprising the nucleic acid molecule of item 88. A host and / or a host cell comprising the nucleic acid molecule according to item 88 and / or the nucleic acid vector according to item 89. A method for the production of a monoclonal antibody, a multivalent antibody, an antigenbinding fragment thereof, and / or a polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment, wherein said method comprises culturing the host and / or the host cell of item 90. A cell-free transcription-translation system or cell-free transcription system or cell-free translation system comprising the nucleic acid molecule according to item 88 and / or the nucleic acid vector according to item 89. A method for the production a monoclonal antibody, a multivalent antibody, an antigenbinding fragment thereof, and / or a polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment, wherein the method comprises a step of transcribing and / or translating the nucleic acid molecule according to item 88 and / or the nucleic acid vector according to item 89 in vitro., in particular with the cell-free transcription-translation system or the cell-free transcription system or the cell-free translation system according to item 92. The method according to item 91 or 93, wherein said method further comprises purifying the monoclonal antibody, the multivalent antibody, the antigen-binding fragment thereof, and / or the polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment. The method according to any one of items 91, 93, and 94, wherein said method further comprises labelling the monoclonal antibody, the multivalent antibody, the antigenbinding fragment thereof, and / or the polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment. Use of the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of item 66 to 86 in the manufacture of a diagnostic composition. A composition comprising the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of items 66 to 86. A kit comprising the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of item 66 to 86, optionally magnetic beads coated with a complexing reagent, and optionally wherein said complexing reagent is streptavidin.. An apparatus comprising: a) the monoclonal antibody according to any one of items 1 to 65; b) the monoclonal antibody according to any one of items 66 to 86; c) a contacting unit for contacting a sample with the monoclonal antibody according to a) and / or with the monoclonal antibody according to b); and / or d) a detecting unit for detecting and / or quantifying the binding of the monoclonal antibody according to a) and / or of the monoclonal antibody according to b). A biosensor comprising the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of items 66 to 86. Use of the monoclonal antibody according to any one of items 1 to 65, the monoclonal antibody according to any one of items 66 to 86, the composition according to item 97, the kit according to item 98, the apparatus according to item 99, and / or the biosensor according to item 100 for the in vitro detection and / or the in vitro quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) in a sample of a subject, preferably in an in vitro immunoassay. The use according to item 101, wherein the in vitro detection and / or the in vitro quantification of the one or more gastrin(s) and / or the one or more cholecystokinin(s)comprises the in vitro detection and / or the in vitro quantification of the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s). An in vitro immunoassay method for the detection and / or for the quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), wherein the method comprises the steps of: a) contacting a sample of a subject with the monoclonal antibody according to any one of items 1 to 65 and / or the monoclonal antibody according to any one of items 66 to 86; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s). The use according to item 101 or 102, or the method according to item 103, wherein the sample is a body fluid sample, preferably a blood sample, more preferably a plasma sample or a serum sample. The use according to any one of items 101, 102, and 104, or the method according to item 103 or 104, wherein at least one of said one or more monoclonal antibodies further comprises a detection label, preferably wherein said detection label is selected from the group consisting of an enzyme, a label emitting light, a label emitting radioactivity and / or a label absorbing light and / or wherein at least one of said one or more monoclonal antibodies further comprises a capture label, preferably wherein said capture label is biotin . The use according to any one of items 101, 102, 104, and 105, or the method according to any one of items 103 to 105, wherein the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s) is quantified by detecting and / or quantifying the amount of said one or more antibodies bound to said one or more gastrin(s) and / or said one or more cholecystokinin(s)via said detection label. The use according to any one of items 101, 102, and 104 to 106, or the method according to any one of items 103 to 106, wherein said in vitro immunoassay comprises the detection and / or quantification of said gastrin with the monoclonal antibody according to any one of items 1 to 65 and the monoclonal antibody according to any one of items 66 to 86. The use according to any one of items 101, 102, and 104 to 107, or the method according to any one of items 103 to 107, wherein the monoclonal antibody according to any one of items 1 to 65 is a detection antibody and the monoclonal antibody according to any one of items 66 to 86 is a capture antibody or wherein the monoclonal antibody according to any one of items 1 to 65 is a capture antibody and the monoclonal antibody according to any one of items 66 to 86 is a detection antibody. The use according to any one of items 101, 102, and 104 to 108, or the method according to any one of items 103 to 108, wherein said in vitro immunoassay is a heterogeneous immunoassay. The use according to any one of items 101, 102, and 104 to 109, or the method according to any one of items 103 to 109, wherein said in vitro immunoassay is a sandwich immunoassay. The use according to any one of items 101, 102, and 104 to 110, or the method according to any one of items 103 to 110, wherein the in vitro immunoassay specifically detects and / or specifically quantifies gastrin 17 using at least the monoclonal antibody according to any one of items 66 to 86. The use according to any one of items 101, 102, and 104 to 111, or the method according to any one of items 103 to 111, wherein the in vitro immunoassay specifically detects and / or specifically quantifies amidated gastrin 17 using the monoclonal antibody according to any one of items 1 to 65 and the monoclonal antibody according to any one of items 66 to 86. The use according to any one of items 101, 102, and 104 to 112, or the method according to any one of items 103 to 112, wherein said in vitro immunoassay specifically detects and / or quantifies amidated gastrin 17 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 56 to 58 and 60. The use according to any one of items 101, 102, and 104 to 113, or the method according to any one of items 103 to 113, wherein said in vitro immunoassay does not detect CCK33 or any precursor thereof or cleavage product thereof. The use according to any one of items 101, 102, and 104 to 114, or the method according to any one of items 104 to 114, wherein said in vitro immunoassay does not detect gastrin 34 or any precursor thereof or any cleavage product thereof except for amidated G17. The use according to any one of items 101, 102, and 104 to 115, or the method according to any one of items 103 to 115, wherein said in vitro immunoassay does not detect gastrin 13. The use according to any one of items 101, 102, and 104 to 116, or the method according to any one of items 103 to 116, wherein said in vitro immunoassay detects and / or quantifies sulfated gastrin 17 with about 91.6% to about 110% sensitivity as compared to non-sulfated gastrin 17. The use according to any one of items 101, 102, and 104 to 117, or the method according to any one of items 103 to 117, wherein said in vitro immunoassay comprises a limit of blank (LoB) of about 0.3 pmol / L or lower. The use according to any one of items 101, 102, and 104 to 118, or the method according to any one of items 103 to 118, wherein said in vitro immunoassay comprises a limit of detection (LoD) of about 0.5 pmol / L or lower. The use according to any one of items 101, 102, and 104 to 119, or the method according to any one of items 103 to 119, wherein said in vitro immunoassay comprises a limit of quantification (LoQ) at 20% CV of about 0.5 pmol / L or lower. 121. The use according to any one of items 101, 102, and 104 to 120, or the method according to any one of items 108 to 126, wherein said in vitro immunoassay comprises a within run coefficient of variation (CV) of about 1.4% or lower as evaluated using samples having gastrin- 17 concentrations between 1.12 pmol / L and 73.1 pmol / L.

[0070] 122. The use according to any one of items 101, 102, and 104 to 121, or the method according to any one of items 103 to 121, wherein said in vitro immunoassay requires about or less than about 30 pL sample volume.

[0071] In a first aspect, the present invention provides for a monoclonal antibody binding to the C- terminus of C-terminally amidated gastrin 17.

[0072] In one embodiment, said monoclonal antibody is a monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence of YMGWMDF (SEQ ID NO: 96) or YGWMDF (SEQ ID NO: 92), preferably wherein said antigen is comprised in C-terminally amidated gastrin or C-terminally amidated cholecystokinin (CCK33), wherein F in position 7 in SEQ ID NO: 96 or F in position 6 in SEQ ID NO: 92 is C-terminally amidated, wherein the sulfur atom comprised in the sulfide group of M in position 5 in SEQ ID NO: 96 or of M in position 4 in SEQ ID NO: 92 may be oxidized, wherein the side chain of Y in position 1 in SEQ ID NO: 96 or of Y in position 1 in SEQ ID NO: 92 may be O-sulfated.

[0073] In this context, the binding of the monoclonal antibody provided in this aspect to said antigen depends on the amidation of the C-terminal phenylalanine residue (i.e., “F” in YMGWMDF or YGWMDF). In other words, said monoclonal antibody specifically binds to C-terminally amidated gastrin 17, e.g., specifically binds to the C-terminal phenylalanine residue if the residue is amidated and / or does not specifically bind to the C-terminal phenylalanine residue if the residue is not amidated.

[0074] In another embodiment, said monoclonal antibody specifically binds to an antigen comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98. The monoclonal antibody may specifically bind to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98.

[0075] In another embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized.

[0076] In a further embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0077] In another embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized.

[0078] In a further embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0079] In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to the herein above detailed epitope via their amino acid sidechains. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0080] Accordingly, in one preferred embodiment, the present invention provides for a monoclonal antibody specifically binding to an epitope consisting of an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0081] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0082] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: i. a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, ii. a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant of SEQ ID NO: 4 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, iii. a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, iv. a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, v. a CDR-L2, and vi. a CDR-L3 comprising or consisting of the amino acid sequence SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33.

[0083] Preferably, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15.

[0084] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, SEQ ID NO: 32, or a variant of SEQ ID NO: 14 or SEQ ID NO: 32 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 14 or SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33.

[0085] Preferably, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with amino acid substitutions in position 1 and / or 4 of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15.

[0086] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody may preferably comprise a VH with W in position 47 of and wherein said position is indicated according to the Kabat numbering scheme.

[0087] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 26, or a variant of SEQ ID NO: 6 or SEQ ID NO: 26 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 6 or SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 27, or a variant of SEQ ID NO: 7 or SEQ ID NO: 27 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 7 or SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 28, or a variant of SEQ ID NO: 8 or SEQ ID NO: 28 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 8 or SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant of SEQ ID NO: 9 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 34, or a variant of SEQ ID NO: 16 or SEQ ID NO: 34 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 16 or SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 35, or a variant of SEQ ID NO: 17 or SEQ ID NO: 35 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 17 or SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant of SEQ ID NO: 18 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant of SEQ ID NO: 19 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0088] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with amino acid substitutions in one or more positions selected from positions 5, 15, 19, 21, and 24 of SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with an amino acid substitution in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with amino acid substitutions in position 10 and / or 13 of SEQ ID NO: 8 and comprising a deletion in position 9 of SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with an amino acid substitution in position 16 of SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with amino acid substitutions in position 2 and / or 6 of SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii. the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0089] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 23, or a variant of SEQ ID NO: 2 or SEQ ID NO: 23 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 2 or SEQ ID NO: 23, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 30, or a variant of SEQ ID NO: 12 or SEQ ID NO: 30 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 12 or SEQ ID NO: 30.

[0090] The monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20.

[0091] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0092] In the context of the present invention, said monoclonal antibody may comprise or consist of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i. the VH as detailed herein above in this aspect, and ii. the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii. the VL as detailed herein above in this aspect, and iv. the CL as detailed herein above in this aspect.

[0093] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises an Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 21 and 36.

[0094] Preferably, the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence selected from any one of SEQ IDs NO: 1 and 22, and wherein said light chain comprises an amino acid sequence selected from any one of SEQ IDs NO: 11 and 29.

[0095] As mentioned herein above and as detailed in the enclosed examples, the inventive monoclonal antibody provided in this aspect comprises advantageous and unforeseeable characteristics. As is detailed herein below, the structurally related monoclonal antibodies 9G1 and 7G7 both effectively bind to amidated gastrin 17 and share comparable characteristics. Example 6 clearly illustrates that said monoclonal antibody binds to amidated (i.e., bioactive) gastrin, however, does not bind to non-amidated gastrin. Accordingly, the monoclonal antibody provided in this aspect does not bind to C-terminally non-amidated gastrin, preferably as determined by a Surface Plasmon Resonance Spectroscopy (SPR) BIAcore binding kinetic measurement, preferably wherein said C-terminally non-amidated gastrin comprises or consists of an amino acid sequence as defined in SEQ ID NO: 85, more preferably wherein said C-terminally non-amidated gastrin consists of an amino acid sequence as defined in SEQ ID NO: 85.

[0096] Example 6 further illustratively demonstrates that the monoclonal antibody provided in this aspect comprises advantageous binding characteristics (i.e., association rate constant, dissociation rate constant, and equilibrium dissociation constant), when contacted with an amidated gastrin.

[0097] Accordingly, said monoclonal antibody comprises an advantageous (i.e., high) association rate constant. Accordingly, said monoclonal antibody comprises an association rate constant ka) of about or at least about 1.21 x 106M^s'1to when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kais determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0098] Further, said monoclonal antibody comprises an advantageous (i.e., low) dissociation rate constant.

[0099] Accordingly, said monoclonal antibody comprises a dissociation rate constant k of about or less than about 5.05 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kd is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0100] Furthermore, said monoclonal antibody comprises an advantageous (i.e., low) equilibrium dissociation constant. Accordingly, said monoclonal antibody comprises an equilibrium dissociation constant (KD) of about or less than about 4.17 x 10'10M when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0101] As detailed herein above, the present invention provides for monoclonal antibodies that effectively bind to the C-terminus of both sulfated (as exemplified in SEQ ID NO: 60) and non-sulfated (as exemplified in SEQ ID NO: 57) amidated gastrin 17. This is, inter alia, illustratively shown in enclosed Example 6. Thus, the monoclonal antibody as provided in this aspect is particularly useful for detecting amidated gastrin 17 irrespective of additional posttranslational modifications. Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the Az? differs by about or less than about 25%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement. In other words, when quantifying the binding of the monoclonal antibody provided in this aspect to the C-terminus of sulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 60) and to the C-terminus of nonsulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 57), preferably using a SPR BIAcore binding kinetic measurement, the resulting KD differs by about or less than about 25%. This is particularly advantageous for the efficient detection of both sulfated and non-sulfated amidated gastrin 17. Preferably such KD measurements are conducted as detailed in Example 6 herein below. The KD values of the herein provided monoclonal antibodies are detailed in Table 3.

[0102] Similarly, and as detailed in the enclosed Example 6, said monoclonal antibody effectively binds to the C-terminus of amidated gastrin 17 comprising either an O-sulfated methionine side chain (as exemplified in SEQ ID NO: 75) or a non-O-sulfated methionine side chain (as exemplified in SEQ ID NO: 77). Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 72%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement.

[0103] In another aspect, the present invention provides for monoclonal antibodies binding to the C- terminus of C-terminally amidated gastrin 17. In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to an epitope via their amino acid sidechains, preferably said epitope consists of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0104] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Preferably, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0105] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33.

[0106] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15.

[0107] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, SEQ ID NO: 32, or a variant of SEQ ID NO: 14 or SEQ ID NO: 32 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 14 or SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33.

[0108] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with amino acid substitutions in position 1 and / or 4 of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15.

[0109] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody may preferably comprise a VH with W in position 47 of and wherein said position is indicated according to the Kabat numbering scheme.

[0110] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 26, or a variant of SEQ ID NO: 6 or SEQ ID NO: 26 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 6 or SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 27, or a variant of SEQ ID NO: 7 or SEQ ID NO: 27 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 7 or SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 28, or a variant of SEQ ID NO: 8 or SEQ ID NO: 28 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 8 or SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant of SEQ ID NO: 9 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 34, or a variant of SEQ ID NO: 16 or SEQ ID NO: 34 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 16 or SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 35, or a variant of SEQ ID NO: 17 or SEQ ID NO: 35 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 17 or SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant of SEQ ID NO: 18 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant of SEQ ID NO: 19 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0111] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with amino acid substitutions in one or more positions selected from positions 5, 15, 19, 21, and 24 of SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with an amino acid substitution in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with amino acid substitutions in position 10 and / or 13 of SEQ ID NO: 8 and comprising a deletion in position 9 of SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with an amino acid substitution in position 16 of SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with amino acid substitutions in position 2 and / or 6 of SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0112] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i. the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii. the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii. the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv. the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0113] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 23, or a variant of SEQ ID NO: 2 or SEQ ID NO: 23 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 2 or SEQ ID NO: 23, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 30, or a variant of SEQ ID NO: 12 or SEQ ID NO: 30 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 12 or SEQ ID NO: 30. In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20.

[0114] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0115] In the context of the present invention, said monoclonal antibody may comprise or consist of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i. the VH as detailed herein above in this aspect, and ii. the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii. the VL as detailed herein above in this aspect, and iv. the CL as detailed herein above in this aspect.

[0116] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises an Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 21 and 36. Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence selected from any one of SEQ IDs NO: 1 and 22, and wherein said light chain comprises an amino acid sequence selected from any one of SEQ IDs NO: 11 and 29.

[0117] In a further aspect, the present invention provides for a monoclonal antibody binding to the C- terminus of C-terminally amidated gastrin 17.

[0118] In one embodiment, said monoclonal antibody is a monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence of: YMGWMDF (SEQ ID NO: 96) or YGWMDF (SEQ ID NO: 92), preferably wherein said antigen is comprised in C-terminally amidated gastrin or C-terminally amidated cholecystokinin (CCK33), wherein F in position 7 in SEQ ID NO: 96 or F in position 6 in SEQ ID NO: 92 is C-terminally amidated, wherein the sulfur atom comprised in the sulfide group of M in position 5 in SEQ ID NO: 96 or of M in position 4 in SEQ ID NO: 92 may be oxidized, wherein the side chain of Y in position 1 in SEQ ID NO: 96 or of Y in position 1 in SEQ ID NO: 92 may be O-sulfated.

[0119] In this context, the binding of the monoclonal antibody provided in this aspect to said antigen depends on the amidation of the C-terminal phenylalanine residue (i.e., “F” in YMGWMDF or YGWMDF). In other words, said monoclonal antibody specifically binds to C-terminally amidated gastrin 17, e.g., specifically binds to the C-terminal phenylalanine residue if the residue is amidated and / or does not specifically bind to the C-terminal phenylalanine residue if the residue is not amidated.

[0120] In another embodiment, said monoclonal antibody specifically binds to an antigen comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98. The monoclonal antibody may specifically bind to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98.

[0121] In another embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized. In a further embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0122] In another embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized.

[0123] In a further embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0124] In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to the herein above detailed epitope via their amino acid sidechains. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0125] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15. Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 , b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 , e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

[0126] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15.

[0127] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

[0128] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0129] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 7, preferably a variant with W in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0130] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0131] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0132] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant of SEQ ID NO: 2 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 2, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant of SEQ ID NO: 12 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 12.

[0133] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20. Preferably said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0134] In the context of the present invention, said monoclonal antibody may comprise or consist of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: i.the VL as detailed herein above in this aspect, and ii.the CL as detailed herein above in this aspect.

[0135] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 21.

[0136] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 1, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 11.

[0137] As mentioned herein above and as detailed in the enclosed examples, the inventive monoclonal antibody provided in this aspect comprises advantageous and unforeseeable characteristics. As is detailed herein below, the structurally related monoclonal antibodies 9G1 and 7G7 both effectively bind to amidated gastrin 17 and share comparable characteristics.

[0138] Example 6 clearly illustrates that said monoclonal antibody binds to amidated (i.e., bioactive) gastrin, however, does not bind to non-amidated gastrin. Accordingly, the monoclonal antibody does not bind to C-terminally non-amidated gastrin. In one embodiment, the monoclonal antibody does not bind to C-terminally non-amidated gastrin, as determined by a Surface Plasmon Resonance Spectroscopy (SPR) BIAcore binding kinetic measurement, preferably wherein said C- terminally non-amidated gastrin comprises or consists of an amino acid sequence as defined in SEQ IDs NO: 85, more preferably wherein said C-terminally non-amidated gastrin consists of an amino acid sequence as defined in SEQ ID NO: 85.

[0139] Example 6 further illustratively demonstrates that the monoclonal antibody provided in this aspect comprises advantageous binding characteristics (i.e., association rate constant, dissociation rate constant, and equilibrium dissociation constant), when contacted with a amidated gastrin.

[0140] Accordingly, said monoclonal antibody comprises an advantageous (i.e., high) association rate constant. Accordingly, said monoclonal antibody comprises an association rate constant (ka) of about or at least about 1.89 x 106M^s'1± about 0.03 x 106M^s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kais determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0141] Further, said monoclonal antibody comprises an advantageous (i.e., low) dissociation rate constant.

[0142] Accordingly, said monoclonal antibody comprises an dissociation rate constant kd of about or less than about 1.90 x 10'4s'1± about 0.01 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kd is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0143] Furthermore, said monoclonal antibody comprises an advantageous (i.e., low) equilibrium dissociation constant. Accordingly, said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 9.60 x 10'11M ± about 0.1 x 10'11M when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0144] As detailed herein above, the present invention provides for monoclonal antibodies that effectively bind to the C-terminus of both sulfated (as exemplified in SEQ ID NO: 60) and non-sulfated (as exemplified in SEQ ID NO: 57) amidated gastrin 17. This is, inter alia, illustratively shown in enclosed Example 6. Thus, the monoclonal antibody as provided in this aspect is particularly useful for detecting amidated gastrin 17 irrespective of additional posttranslational modifications. Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the Az? differs by about or less than about 16%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement. In other words, when quantifying the binding of the monoclonal antibody provided in this aspect to the C-terminus of sulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 60) and to the C-terminus of nonsulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 57), preferably using a SPR BIAcore binding kinetic measurement, the resulting KD differs by about or less than about 16%. This is particularly advantageous for the efficient detection of both sulfated and non-sulfated amidated gastrin 17. Preferably such KD measurements are conducted as detailed in Example 6 herein below. The KD values of the herein provided monoclonal antibodies are detailed in Table 3.

[0145] Similarly, and as detailed in the enclosed Example 6, said monoclonal antibody effectively binds to the C-terminus of amidated gastrin 17 comprising either an O-sulfated methionine side chain (as exemplified in SEQ ID NO: 75) or a non-O-sulfated methionine side chain (as exemplified in SEQ ID NO: 77). Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 41%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement.

[0146] In another aspect, the present invention provides for monoclonal antibodies binding to the C- terminus of C-terminally amidated gastrin 17.

[0147] In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to an epitope via their amino acid sidechains, preferably said epitope consists of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0148] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y in position 32; Y in position 91; V in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0149] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15.

[0150] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 , b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 , e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

[0151] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 15.

[0152] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

[0153] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0154] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 7, preferably a variant with W in position 8 of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0155] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 16, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 17, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0156] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0157] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 2, or a variant of SEQ ID NO: 2 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 2, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, or a variant of SEQ ID NO: 12 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 12.

[0158] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20.

[0159] Preferably said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0160] In the context of the present invention, said monoclonal antibody may comprise or consist of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii.the VL as detailed herein above in this aspect, and iv.the CL as detailed herein above in this aspect. The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 21.

[0161] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 1, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 11.

[0162] In a further aspect, the present invention provides for a monoclonal antibody binding to the C- terminus of C-terminally amidated gastrin 17.

[0163] In one embodiment, said monoclonal antibody is a monoclonal antibody specifically binding to an antigen comprising or consisting of an amino acid sequence of: YMGWMDF (SEQ ID NO: 96) or YGWMDF (SEQ ID NO: 92), wherein said antigen is comprised in C-terminally amidated gastrin or C-terminally amidated cholecystokinin (CCK33), wherein F in position 7 in SEQ ID NO: 96 or F in position 6 in SEQ ID NO: 92 is C-terminally amidated, wherein the sulfur atom comprised in the sulfide group of M in position 5 in SEQ ID NO: 96 or of M in position 4 in SEQ ID NO: 92 may be oxidized, wherein the side chain of Y in position 1 in SEQ ID NO: 96 or of Y in position 1 in SEQ ID NO: 92 may be O-sulfated.

[0164] In this context, the binding of the monoclonal antibody provided in this aspect to said antigen depends on the amidation of the C-terminal phenylalanine residue (i.e., “F” in YMGWMDF or YGWMDF). In other words, said monoclonal antibody specifically binds to C-terminally amidated gastrin 17 e.g. specifically binds to the C-terminal phenylalanine residue if the residue is amidated and / or does not specifically bind to the C-terminal phenylalanine residue if the residue is not amidated.

[0165] In another embodiment, said monoclonal antibody specifically binds to an antigen comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98. The monoclonal antibody may specifically bind to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 89 to 98.

[0166] In another embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized. In a further embodiment, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0167] In another embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence of: GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized.

[0168] In a further embodiment, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0169] In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to the herein above detailed epitope via their amino acid sidechains. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; W in position 32; Y in position 91; D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0170] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme. As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 of the monoclonal antibody 9G1 is contributing to the binding of said epitope. Given the similarities in the sequence of the monoclonal antibodies 9G1 and 7G7 (i.e., a monoclonal antibody in accordance with this aspect; i.e., more than about 90% sequence similarity between the complete sequences of both monoclonal antibodies) and in particular their CDRs of the heavy chain and the CDRs LI and L3 as well as the structural data for 9G1 indicating that CDR-L2 does not contribute to the antigen binding, it is conceivable that also for the monoclonal antibody of this aspect (i.e., a monoclonal antibody as exemplified by antibody 7G7 of the enclosed examples) the CDR-L2 does not contribute to the binding of the antigen. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 33.

[0171] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33.

[0172] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 33.

[0173] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33.

[0174] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0175] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 27, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0176] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19. As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0177] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant of SEQ ID NO: 23 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 23, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, or a variant of SEQ ID NO: 30 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 30.

[0178] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20.

[0179] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0180] In the context of the present invention, said monoclonal antibody comprises or consists of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii.the VL as detailed herein above in this aspect, and iv.the CL as detailed herein above in this aspect.

[0181] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 36.

[0182] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 22, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 29.

[0183] As mentioned herein above and as detailed in the enclosed examples, the inventive monoclonal antibody provided in this aspect comprises advantageous and unforeseeable characteristics. As is detailed herein below, the structurally related monoclonal antibodies 9G1 and 7G7 both effectively bind to amidated gastrin 17 and share comparable characteristics. Example 6 clearly illustrates that said monoclonal antibody binds to amidated (i.e., bioactive) gastrin, however, does not bind to non-amidated gastrin. Accordingly, the monoclonal antibody provided in this aspect does not bind to C-terminally non-amidated gastrin. In one embodiment, the monoclonal antibody provided in this aspect does not bind to C-terminally non-amidated gastrin, as determined by a Surface Plasmon Resonance Spectroscopy (SPR) BIAcore binding kinetic measurement, preferably wherein said C-terminally non-amidated gastrin comprises or consists of an amino acid sequence as defined in SEQ ID NO: 85, more preferably wherein said C-terminally non-amidated gastrin consists of an amino acid sequence as defined in SEQ ID NO: 85.

[0184] Example 6 further illustratively demonstrates that the monoclonal antibody provided in this aspect comprises advantageous binding characteristics (i.e., association rate constant, dissociation rate constant, and equilibrium dissociation constant), when contacted with a amidated gastrin.

[0185] Accordingly, said monoclonal antibody comprises an advantageous (i.e., high) association rate constant. Accordingly, said monoclonal antibody comprises an association rate constant ka) of about or at least about 1.21 x 106M^s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kais determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0186] Further, said monoclonal antibody comprises an advantageous (i.e., low) dissociation rate constant.

[0187] Accordingly, said monoclonal antibody comprises an dissociation rate constant k of about or less than about 5.05 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kd is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0188] Furthermore, said monoclonal antibody comprises an advantageous (i.e., low) equilibrium dissociation constant. Accordingly, said monoclonal antibody comprises an equilibrium dissociation constant (KD) of about or less than about 4.17 x IO'10M when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in any one of SEQ IDs NO: 57, 60, 75, 77, 82, and 83.

[0189] As detailed herein above, the present invention provides for monoclonal antibodies that effectively bind to the C-terminus of both sulfated (as exemplified in SEQ ID NO: 60) and non-sulfated (as exemplified in SEQ ID NO: 57) amidated gastrin 17. This is, inter alia, illustratively shown in enclosed Example 6. Thus, the monoclonal antibody as provided in this aspect is particularly useful for detecting amidated gastrin 17 irrespective of additional posttranslational modifications. Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the Az? differs by about or less than about 25%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement. In other words, when quantifying the binding of the monoclonal antibody provided in this aspect to the C-terminus of sulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 60) and to the C-terminus of nonsulfated amidated gastrin 17 (as exemplified in SEQ ID NO: 57), preferably using a SPR BIAcore binding kinetic measurement, the resulting KD differs by about or less than about 16%. This is particularly advantageous for the efficient detection of both sulfated and non-sulfated amidated gastrin 17. Preferably such KD measurements are conducted as detailed in Example 6 herein below. The KD values of the herein provided monoclonal antibodies are detailed in Table 3.

[0190] Similarly, and as detailed in the enclosed Example 6, said monoclonal antibody effectively binds to the C-terminus of amidated gastrin 17 comprising either an O-sulfated methionine side chain (as exemplified in SEQ ID NO: 75) or a non-O-sulfated methionine side chain (as exemplified in SEQ ID NO: 77). Accordingly, when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 75 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 77, the KD differs by about or less than about 71%, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement.

[0191] In another aspect, the present invention provides for monoclonal antibodies binding to the C- terminus of C-terminally amidated gastrin 17. In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to an epitope via their amino acid sidechains, preferably said epitope consists of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

[0192] Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; W in position 32; Y in position 91; D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0193] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising S in position 34; Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 96; V in position 97; N in position 98; S in position 99; G in position 100; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0194] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 14, that no amino acid residue of CDR-L2 of the monoclonal antibody 9G9 is contributing to the binding of said epitope. Given the similarities in the sequence of the monoclonal antibodies 9G1 and 7G7 (i.e., a monoclonal antibody in accordance with this aspect; i.e., more than about 90% sequence similarity between the complete sequences of both monoclonal antibodies) and in particular their CDRs of the heavy chain and the CDRs LI and L3 as well as the structural data for 9G1 indicating that CDR-L2 does not contribute to the antigen binding, it is conceivable that also for the monoclonal antibody of this aspect (i.e., a monoclonal antibody as exemplified by antibody 7G7 of the enclosed examples) the CDR-L2 does not contribute to the binding of the antigen. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 33.

[0195] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33.

[0196] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 33.

[0197] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33.

[0198] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0199] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 27, preferably a variant with W in position 8 of SEQ ID NO: 27, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0200] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 26, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 27, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 28, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 34, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 35, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 18, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0201] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0202] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 23, or a variant of SEQ ID NO: 23 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 23, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, or a variant of SEQ ID NO: 30 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 30.

[0203] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 20.

[0204] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 10; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 20.

[0205] In the context of the present invention, said monoclonal antibody comprises or consists of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii.the VL as detailed herein above in this aspect, and iv.the CL as detailed herein above in this aspect.

[0206] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 36.

[0207] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 22, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 29.

[0208] In a further aspect, the present invention provides for inventive monoclonal antibodies that specifically bind to gastrin 17. Namely, said monoclonal antibody specifically binds to gastrin 17 comprising an N-terminal pyroglutamate residue.

[0209] Accordingly, said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence of: XGPWLEE (SEQ ID NO: 99), wherein X in position 1 in SEQ ID NO: 99 is a pyroglutamate residue. Accordingly, in another embodiment said monoclonal antibody specifically binds to an epitope comprising or consisting of an amino acid sequence of SEQ ID NO: 99.

[0210] Accordingly, said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence of: XGPWLEE (SEQ ID NO: 99), wherein X in position 1 in SEQ ID NO: 99 is a pyroglutamate residue. Accordingly, in another embodiment said monoclonal antibody specifically binds to an epitope comprised in an amino acid sequence of SEQ ID NO: 99. In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to the herein above detailed epitope via their amino acid sidechains. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; W in position 58; D in position 95; Y in position 96; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0211] Accordingly, in one preferred embodiment, the present invention provides for a monoclonal antibody specifically binding to gastrin 17 comprising an N-terminal pyroglutamate residue, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; W in position 58; D in position 95; Y in position 96; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0212] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; I in position 52A; R in position 53; W in position 58; D in position 95; Y in position 96; A in position 97; G in position 98; G in position 99; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; A in position 92; T in position 93; Y in position 94; T in position 95; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0213] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 15, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 48, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 50.

[0214] Preferably, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50.

[0215] In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 48, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 49, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 50.

[0216] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50.

[0217] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0218] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 42, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 43, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 44 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 51, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 52, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 53, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0219] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 43, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0220] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect.

[0221] Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 38, or a variant of SEQ ID NO: 38 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 38, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 47, or a variant of SEQ ID NO: 47 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 47.

[0222] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 54.

[0223] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54.

[0224] In the context of the present invention, said monoclonal antibody comprises or consists of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: c) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and d) a light chain comprising or consisting of: iii.the VL as detailed herein above in this aspect, and iv.the CL as detailed herein above in this aspect.

[0225] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 55.

[0226] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 37, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 46.

[0227] As mentioned herein above and as detailed in the enclosed examples, the inventive monoclonal antibody provided in this aspect comprises advantageous and unforeseeable characteristics. As is detailed herein below, the structurally related monoclonal antibody 41G5 effectively binds to (amidated) gastrin 17, however, does not bind to CCK33 or gastrin 34.

[0228] Example 6 clearly illustrates that said monoclonal antibody binds to gastrin 17, however, does not bind to CCK33 (as exemplified in SEQ ID NO: 84). Accordingly, the monoclonal antibody provided in this aspect does not bind to CCK33. In one embodiment, the monoclonal antibody provided in this aspect does not bind to CCK33, as determined by a SPR BIAcore binding kinetic measurement. Preferably, said CCK33 comprises or consists of an amino acid sequence as defined in SEQ ID NO: 84.

[0229] Example 6 clearly illustrates that said monoclonal antibody binds to gastrin 17, however, does not bind to gastrin 34 (as exemplified in SEQ ID NO: 82). Accordingly, the monoclonal antibody provided in this aspect does not bind to gastrin 34. In one embodiment, the monoclonal antibody provided in this aspect does not bind to gastrin 34, as determined by a SPR BIAcore binding kinetic measurement. Preferably, said gastrin 34 comprises or consists of an amino acid sequence as defined in SEQ ID NO: 82.

[0230] Example 6 further illustratively demonstrates that the monoclonal antibody provided in this aspect comprises advantageous binding characteristics (i.e., association rate constant, dissociation rate constant, and equilibrium dissociation constant), when contacted with a amidated gastrin.

[0231] Accordingly, said monoclonal antibody comprises an advantageous (i.e., high) association rate constant. Accordingly, said monoclonal antibody comprises an association rate constant (ka) of about or at least about 4.17 x 106M_|s_|± about 0.05 x 106M_|s_|when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kais determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in SEQ ID NO: 60.

[0232] Further, said monoclonal antibody comprises an advantageous (i.e., low) dissociation rate constant.

[0233] Accordingly, said monoclonal antibody comprises an dissociation rate constant kd of about or less than about 1.29 x 10'4s'1± about 0.01 x 10'4s'1when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein kd is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in SEQ ID NO: 60.

[0234] Furthermore, said monoclonal antibody comprises an advantageous (i.e., low) equilibrium dissociation constant. Accordingly, said monoclonal antibody comprises an equilibrium dissociation constant KD) of about or less than about 3.09 x 10'11M ± about 0.05 x 10'11M when contacted with a polypeptide comprising or consisting of the epitope as detailed herein above in this aspect, preferably wherein KD is determined by a SPR BIAcore binding kinetic measurement, preferably wherein said polypeptide comprises or consists of the amino acid sequence as defined in SEQ ID NO: 60. In a further aspect, the present invention provides for inventive monoclonal antibodies that specifically bind to gastrin 17.

[0235] In the context of the present invention, said monoclonal antibody comprises various amino acid residues that bind to an epitope via their amino acid sidechains, preferably wherein said epitope consists of an amino acid sequence of: XGPWLEE (SEQ ID NO: 99), wherein X in position 1 in SEQ ID NO: 99 is a pyroglutamate residue. Accordingly, in one embodiment, said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; W in position 58; D in position 95; Y in position 96; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0236] It is evident that in addition to the herein above detailed amino acid side chains that are involved in the binding of said epitope, also the backbone of amino acids comprised in said monoclonal antibody may contribute to the binding of the herein above detailed epitope. Accordingly, preferably said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; I in position 52A; R in position 53; W in position 58; D in position 95; Y in position 96; A in position 97; G in position 98; G in position 99; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; A in position 92; T in position 93; Y in position 94; T in position 95; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

[0237] As is further detailed herein below, in particular complementarity determining regions (CDRs) of the heavy chain (i.e., CDR-H1, CDR-H2, and CDR-H3) or of the light chain (i.e., CDR-L1, CDR- L2, and CDR-L3) of monoclonal antibodies are involved in the binding of the herein above detailed epitope. However, in the context of the present aspect, it was found, as is detailed in the enclosed Example 15, that no amino acid residue of CDR-L2 is contributing to the binding of said epitope. Accordingly, in one embodiment said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 48, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 50.

[0238] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50. In a further embodiment, said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 48, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 49, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 50.

[0239] Preferably said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50.

[0240] As detailed in the enclosed Examples, the side chain of a tryptophane residue in position 47 (according to the Kabat numbering scheme) of the VH may contribute to the binding of the epitope. However, it is likely that the binding of the epitope may be sufficiently bound if said tryptophane residue in position 47 is substituted or deleted. Accordingly, in the context of the present invention, said monoclonal antibody may further comprise one or more epitope-binding amino acid residues comprised in one or more framework regions. Accordingly, in any of the herein above detailed embodiments, said monoclonal antibody comprises a VH with W in position 47 and wherein said position is indicated according to the Kabat numbering scheme.

[0241] As mentioned herein above and further detailed herein below, monoclonal antibodies comprise four framework regions in their heavy chain (FW-H1 to FW-H4) and four framework regions in their light chain (FW-L1 to FW-L4). Accordingly, in any of the herein above embodiments, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 42, b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 43, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 44 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 4, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 51, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 52, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 53, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 19.

[0242] In any of the embodiments of the present invention detailed herein above, said monoclonal antibody may comprise: a) a first heavy chain framework region (FW-H1) N-terminal to said CDR-H1, wherein said FW-H1 comprises or consists of the amino acid sequence of SEQ ID NO: 42, Il l b) a second heavy chain framework region (FW-H2) N-terminal to said CDR-H2 and C- terminal to said CDR-H1, wherein said FW-H2 comprises or consists of the amino acid sequence of SEQ ID NO: 43, c) a third heavy chain framework region (FW-H3) N-terminal to said CDR-H3 and C-terminal to said CDR-H2, wherein said FW-H3 comprises or consists of the amino acid sequence of SEQ ID NO: 43, d) a fourth heavy chain framework region (FW-H4) C-terminal to said CDR-H3, wherein said FW-H4 comprises or consists of the amino acid sequence of SEQ ID NO: 9, e) a first light chain framework region (FW-L1) N-terminal to said CDR-L1, wherein said FW-L1 comprises or consists of the amino acid sequence of SEQ ID NO: 51, f) a second light chain framework region (FW-L2) N-terminal to said CDR-L2 and C- terminal to said CDR-L1, wherein said FW-L2 comprises or consists of the amino acid sequence of SEQ ID NO: 52, g) a third light chain framework region (FW-L3) N-terminal to said CDR-L3 and C-terminal to said CDR-L2, wherein said FW-L3 comprises or consists of the amino acid sequence of SEQ ID NO: 53, and h) a fourth light chain framework region (FW-L4) C-terminal to said CDR-L3, wherein said FW-L4 comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0243] As will be detailed herein below, the 3 heavy chain complementarity determining regions and the four heavy chain framework regions collectively constitute a heavy chain variable domain (VH). Likewise, the three light chain complementarity determining regions and the four light chain framework regions collectively constitute a light chain variable domain (VL). Accordingly, in another embodiment, the present invention provides for a monoclonal antibody comprising: a) a VH comprising or consisting of: i.the CDR-H1, the CDR-H2, and the CDR-H3 as detailed herein above in this aspect, and ii.the FW-H1, the FW-H2, the FW-H3, and the FW-H4 as detailed herein above in this aspect; and b) a VL comprising or consisting of: iii.the CDR-L1, the CDR-L2, and the CDR-L3 as detailed herein above in this aspect, and iv.the FW-L1, the FW-L2, the FW-L3, and the FW-L4 as detailed herein above in this aspect. Accordingly, in one embodiment of the present invention, said monoclonal antibody may comprise a heavy chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 38, or a variant of SEQ ID NO: 38 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 38, and a light chain variable domain comprising or consisting of the amino acid sequence of SEQ ID NO: 47, or a variant of SEQ ID NO: 47 with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 47.

[0244] In another embodiment, the monoclonal antibody detailed in this aspect may further comprise a heavy chain conserved domain (CHI) N-terminal to said VH and a light chain conserved domain (CL) N-terminal to said VL. Preferably, said monoclonal antibody comprises a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54 or a variant thereof with at least about 90%, preferably with at least about 95%, more preferably with at least about 96%, even more preferably with at least about 97%, even more preferably with at least about 98%, most preferably with at least about 99% amino acid sequence identity to SEQ ID NO: 54.

[0245] Preferably, said monoclonal antibody comprises: a) a heavy chain conserved domain (CHI) N-terminal to said VH, wherein said CHI comprises or consists of an amino acid sequence according to SEQ ID NO: 45; and b) a light chain conserved domain (CL) N-terminal to said VL, wherein said CL comprises or consists of an amino acid sequence according to SEQ ID NO: 54.

[0246] In the context of the present invention, said monoclonal antibody comprises or consists of a Fragment Antigen Binding region (Fab region). In one embodiment, said Fab region comprises or consists of: a) a Fab region heavy chain comprising or consisting of: i.the VH as detailed herein above in this aspect, and ii.the CHI as detailed herein above in this aspect; and b) a light chain comprising or consisting of: iii.the VL as detailed herein above in this aspect, and iv.the CL as detailed herein above in this aspect.

[0247] The monoclonal antibody of this aspect may further comprise a fragment crystallizable region (Fc region). Preferably, said monoclonal antibody comprises a Fc region comprising or consisting of an amino acid sequence selected from SEQ ID NO: 55.

[0248] Preferably the herein provided monoclonal antibody comprises or consists of a heavy chain and a light chain, wherein said heavy chain comprises an amino acid sequence of SEQ ID NO: 37, and wherein said light chain comprises an amino acid sequence of SEQ ID NO: 46.

[0249] In the above aspects, any of the herein above detailed antibodies may be a full immunoglobulin (i.e., comprising two Fab regions and an Fc region), Fab fragment, a F(ab')2 fragment, or a singlechain variable fragment (scFv) fragment. In a specific embodiment, the above detailed antibodies may be a Fab fragment.

[0250] Further, in the context of the present invention, any of the above detailed antibodies or fragments thereof may be incorporated into a chimeric antibody, a CDR-grafted antibody, a bivalent antibody-construct, an antibody-fusion protein, a synthetic antibody, and a multivalent antibody. In a specific embodiment the present invention provides for a multivalent antibody comprising or consisting of the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17.

[0251] The invention also provides for nucleic acid molecules encoding the monoclonal antibodies of the present invention. Accordingly, the present invention provides for a nucleic acid molecule comprising a nucleic acid sequence encoding one or more selected from the group consisting of the following: a) the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N-terminus of gastrin 17; b) the above detailed multivalent antibody; c) an antigen-binding fragment according to a) and / or b); and d) a polypeptide comprising a), b), and / or c).

[0252] Further herein provided are nucleic acid vectors comprising nucleic acid molecules of the invention. In particular, provided herein are nucleic acid vectors comprising a nucleic acid molecule encoding one or more antibodies or one or more antibody fragments of the invention.

[0253] The present invention also provides for a host and / or a host cell comprising a nucleic acid molecule or a nucleic acid vector of the present invention. In particular the host and / or host cell may be procaryotic or eukaryotic. In the context of the present invention the host may not be of human nature. Optionally, said host is procaryotic. It is preferred herein, that the host cell is a eukaryotic cell. In particular, the host cell may be a HEK or CHO cell. Such host cells are particularly useful in the production of the herein provided monoclonal antibodies that are encoded by the nucleic acid molecules and / or nucleic acid vectors provided herein.

[0254] Accordingly, the present invention also provides for a method for the production of a monoclonal antibody, a multivalent antibody, an antigen-binding fragment thereof, and / or a polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment, wherein said method comprises culturing the above detailed host and / or the above detailed host cell.

[0255] The skilled person in the art is aware that monoclonal antibodies that are encoded by the herein provided nucleic acid molecules and / or nucleic acid vectors may also be produced without the need for a host or a host cell. Accordingly, the present invention also provides for a cell-free transcription-translation system or cell-free transcription system or cell-free translation system comprising the above detailed nucleic acid molecule and / or the above detailed nucleic acid vector.

[0256] The present invention further provides for methods that employ said cell-free transcription and / or translation systems. Accordingly, herein provided is a method for the production a monoclonal antibody, a multivalent antibody, an antigen-binding fragment thereof, and / or a polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment, wherein the method comprises a step of transcribing and / or translating an above detailed nucleic acid molecule and / or an above detailed nucleic acid vector in vitro., in particular with the cell-free transcription-translation system or the cell-free transcription system or the cell free translation system as detailed herein above. In one embodiment, the method further comprises purifying the monoclonal antibody, the multivalent antibody, the antigen-binding fragment thereof, and / or the polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment. Antibodies can be purified using standard protein purification methods. Methods for purification of antibodies are well known in the art. Exemplary purification methods are described in the enclosed examples.

[0257] In another embodiment, the method further comprises labelling the monoclonal antibody, the multivalent antibody, the antigen-binding fragment thereof, and / or the polypeptide comprising said monoclonal antibody, said multivalent antibody, and / or said antigen-binding fragment.

[0258] As detailed herein above, the herein provided monoclonal antibodies are particularly useful in diagnostic applications, in particular in the detection of gastrin 17. Accordingly, the present invention also provides for the use of the above detailed monoclonal antibody binding to the C- terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 in the manufacture of a diagnostic composition.

[0259] Accordingly, herein provided is a composition comprising the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N-terminus of gastrin 17. In particular, the composition may be a diagnostic composition.

[0260] Further herein provided is a kit comprising the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N-terminus of gastrin 17, optionally magnetic beads coated with a complexing reagent, and optionally wherein said complexing reagent is streptavidin. The kit may be a kit for detecting and / or quantifying gastrin, in particular gastrin 17 in vitro. In particular, the kit may be an immunoassay kit, preferably, a kit for a heterogeneous immunoassay, more preferably, a kit for a competitive immunoassay.

[0261] Herein, it is further provided for an apparatus comprising antibodies of the present invention.

[0262] Accordingly, the present invention also provides for an apparatus comprising: a) the above detailed monoclonal antibody binding to the C-terminus of gastrin 17; b) the above detailed monoclonal antibody binding to the N-terminus of gastrin 17; c) a contacting unit for contacting a sample with the monoclonal antibody according to a) and / or with the monoclonal antibody according to b); and / or d) a detecting unit for detecting and / or quantifying the binding of the monoclonal antibody according to a) and / or of the monoclonal antibody according to b).

[0263] Furthermore, the present invention provides for a biosensor comprising the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N-terminus of gastrin 17.

[0264] As mentioned herein above, the present invention, inter alia, also provides for diagnostic uses of the herein provided innovative antibodies.

[0265] Accordingly, the present invention provides for the use of the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, the above detailed monoclonal antibody binding to the N- terminus of gastrin 17, the above detailed composition, the above detailed kit, the above detailed apparatus, and / or the above detailed biosensor for the in vitro detection and / or the in vitro quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) in a sample of a subject, preferably in an in vitro immunoassay.

[0266] In one aspect, the present invention provides for the use of the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, the above detailed monoclonal antibody binding to the N- terminus of gastrin 17, the above detailed composition, the above detailed kit, the above detailed apparatus, and / or the above detailed biosensor for the in vitro detection and / or the in vitro quantification of gastrin 17 in a sample of a subject, preferably in an in vitro immunoassay.

[0267] Preferably the present invention provides for the use of the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, the above detailed monoclonal antibody binding to the N- terminus of gastrin 17, the above detailed composition, the above detailed kit, the above detailed apparatus, and / or the above detailed biosensor for the in vitro detection and / or the in vitro quantification of amidated gastrin 17 in a sample of a subject, preferably in an in vitro immunoassay. As detailed herein above, the herein above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is particularly useful in the detection and / or quantification of amidated gastrin 17 (as exemplified in SEQ ID NO: 61), amidated gastrin 34 (as exemplified in SEQ ID NO: 82), and / or amidated CCK33 (as exemplified in SEQ ID NO: 83). As also detailed herein above, the herein above detailed monoclonal antibody binding to the N-terminus of gastrin 17 is particularly useful in the detection and / or quantification of gastrin 17 comprising an N-terminal pyroglutamate residue.

[0268] Accordingly, when using said monoclonal antibody binding to the C-terminus of gastrin 17 and said monoclonal antibody binding to the N-terminus of gastrin 17, or the above detailed composition comprising both monoclonal antibodies, the above detailed kit comprising both monoclonal antibodies, the above detailed apparatus comprising both monoclonal antibodies, or the above detailed biosensor comprising both monoclonal antibodies in the (in vitro) detection and / or the (in vitro) quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), the one or more gastrin(s) and / or the one or more cholecystokinin(s) to be detected and / or quantified is amidated gastrin 17 (whereas for example amidated or non-amidated gastrin 34, amidated or non-amidated CCK33, non-amidated gastrin 17 may not be detected and / or quantified). This is further demonstrated, inter alia, in enclosed Example 6.

[0269] When using only said monoclonal antibody binding to the C-terminus of gastrin 17 or the above detailed composition comprising only said monoclonal antibody binding to the C-terminus of gastrin 17, the above detailed kit comprising only said monoclonal antibody binding to the C- terminus of gastrin 17, the above detailed apparatus comprising only said monoclonal antibody binding to the C-terminus of gastrin 17, or the above detailed biosensor comprising only said monoclonal antibody binding to the C-terminus of gastrin 17 in the (in vitro) detection and / or the (in vitro) quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), the one or more gastrin(s) and / or the one or more cholecystokinin(s) to be detected and / or quantified is an amidated gastrin or an amidated cholecystokinin. This includes, inter alia, amidated gastrin 17, amidated gastrin 34, and amidated CCK33 (whereas for example non-amidated gastrin 34, non- amidated CCK33, non-amidated gastrin 17 may not be detected and / or quantified). This is further demonstrated, inter alia, in enclosed Example 6. In this context, the term “only said monoclonal antibody binding to the C-terminus of gastrin 17” indicates that said monoclonal antibody binding to the C-terminus of gastrin 17 is to be used in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), however, the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 is not to be used in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) in this context. However, the skilled person is aware that other reagents (apart from monoclonal antibodies) may be required in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s). Here, even if “only said monoclonal antibody binding to the C-terminus of gastrin 17” is to be used, this does not exclude any other reagents from being employed in this context. Accordingly, the present invention further relates to the use of the herein above detailed monoclonal antibody binding to the C-terminus of gastrin 17 in the detection and / or quantification of e.g., amidated gastrin 34 and / or amidated CCK33.

[0270] When using only said monoclonal antibody binding to the N-terminus of gastrin 17 or the above detailed composition comprising only said monoclonal antibody binding to the N-terminus of gastrin 17, the above detailed kit comprising only said monoclonal antibody binding to the N- terminus of gastrin 17, the above detailed apparatus comprising only said monoclonal antibody binding to the N-terminus of gastrin 17, or the above detailed biosensor comprising only said monoclonal antibody binding to the N-terminus of gastrin 17 in the (in vitro) detection and / or the (in vitro) quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), the one or more gastrin(s) and / or the one or more cholecystokinin(s) to be detected and / or quantified is gastrin 17. This includes, inter alia, amidated gastrin 17 and non-amidated gastrin 17 (whereas for example amidated or non-amidated gastrin 34 and amidated or non-amidated CCK33 may not be detected and / or quantified). This is further demonstrated, inter alia, in enclosed Example 6. In this context, the term “only said monoclonal antibody binding to the N-terminus of gastrin 17” indicates that said monoclonal antibody binding to the N-terminus of gastrin 17 is to be used in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), however, the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is not to be used in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) in this context. However, the skilled person is aware that other reagents (apart from monoclonal antibodies) may be required in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s). Here, even if “only said monoclonal antibody binding to the C-terminus of gastrin 17” is to be used, this does not exclude any other reagents from being employed in this context. Accordingly, the present invention further relates to the use of the herein above detailed monoclonal antibody binding to the N-terminus of gastrin 17 in the detection and / or quantification of e.g., amidated and / or non-amidated gastrin 17. In the context of the present invention, it is further envisaged that any of the above detailed monoclonal antibodies binding to the C-terminus of gastrin 17 or binding to the N-terminus of gastrin 17 may also be used in combination with any other suitable antibody or antigen-binding fragment thereof that are known in the art for detecting and / or quantifying one or more gastrin(s) and / or one or more cholecystokinin(s) (in particular, gastrin 17 or amidated gastrin 17). The antibody or antigen-binding fragment thereof known in the art are not limited.

[0271] Anything detailed in this aspect of the present invention similarly applies not only to the uses of the herein provided monoclonal antibodies in the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), however, also applies to any in vitro immunoassay for the detection and / or the quantification of a gastrin, as detailed herein below.

[0272] In the above detailed use, the in vitro detection and / or the in vitro quantification of the one or more gastrin(s) and / or the one or more cholecystokinin(s) comprises the in vitro detection and / or the in vitro quantification of the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s).

[0273] Preferably, the sample is a body fluid sample. In the context of the present invention, body fluid samples may be samples comprising one or more body fluids or modified body fluids (this means, inter alia, body fluids that have been concentrated, diluted, buffered, frozen, thawed, and the like). Body fluids may be derived from any animal that could benefit from the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) (e.g., amidated G17) in their body fluids. Preferably, body fluids are derived from humans. Body fluids may be selected from the group consisting of the following: blood, cerebrospinal fluid, seminal fluid, saliva, urine, bile, feces, interstitial fluid. Preferably said body fluid sample is a blood sample. In the context of the present invention, a blood sample may be a serum sample, a plasma sample, or a whole blood sample, preferably a plasma sample or a serum sample.

[0274] Preferably at least one of said one or more monoclonal antibodies further comprises a detection label, preferably wherein said detection label is selected from the group consisting of an enzyme, a label emitting light, a label emitting radioactivity and / or a label absorbing light and / or wherein at least one of said one or more monoclonal antibodies further comprises a capture label, preferably wherein said capture label is biotin. It is further preferred that a monoclonal antibody of the present invention comprises either a detection label or a capture label. Preferably the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s) is quantified by detecting and / or quantifying the amount of said one or more antibodies bound to said one or more gastrin(s) and / or said one or more cholecystokinin(s) via said detection label.

[0275] In a preferred embodiment of the above detailed use, said in vitro immunoassay comprises the detection and / or quantification of said gastrin with the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17. As is detailed herein above and below, when employing the herein above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and the herein above detailed monoclonal antibody binding to the N-terminus of gastrin 17, the gastrin to be detected and / or quantified is amidated gastrin 17.

[0276] In a further preferred embodiment of the above detailed use, the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is a detection antibody and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 is a capture antibody or wherein the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is a capture antibody and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 is a detection antibody.

[0277] In another embodiment of the above detailed use, the in vitro immunoassay is a heterogeneous immunoassay.

[0278] Preferably, the in vitro immunoassay is a sandwich immunoassay.

[0279] As has been detailed herein above the herein provided monoclonal antibodies binding to the C- terminus of gastrin 17 or to the N-terminus of gastrin 17 are particularly useful for the detection of gastrin 17. As is evident from the enclosed examples, the herein provided monoclonal antibody binding to the N-terminus of gastrin 17 is sufficient to discriminate gastrin 17 (comprising an N- terminal pyroglutamate residue, as exemplified, inter alia, in SEQ ID NO: 60) from e.g., gastrin 13, gastrin 34, or CCK33. Accordingly, in a preferred embodiment of the above detailed use, the in vitro immunoassay specifically detects and / or specifically quantifies gastrin 17. Accordingly, said in vitro immunoassay does not detect CCK33 or any precursor thereof or any cleavage product thereof.

[0280] Accordingly, said in vitro immunoassay does not detect gastrin 34 or any precursor thereof or any cleavage product thereof except for amidated G17.

[0281] Accordingly, said in vitro immunoassay does not detect (amidated) gastrin 13.

[0282] As also detailed herein above, the herein provided monoclonal antibodies binding to the C- terminus of gastrin 17, specifically bind to the C-terminus of C-terminally amidated gastrin 17 (as exemplified, inter alia, in SEQ ID NO: 60). Accordingly, in another embodiment of the above detailed use, the in vitro immunoassay specifically detects and / or specifically quantifies amidated gastrin 17.

[0283] Accordingly, in a further embodiment of the above detailed use, said in vitro immunoassay specifically detects and / or quantifies amidated gastrin 17 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 56 to 58 and 60.

[0284] As detailed herein above and as illustratively demonstrated, inter alia, in the enclosed Example 9, the herein provided monoclonal antibodies binding to the C-terminus of gastrin 17 (e.g., 9G1 and / or 7G7) can detect both sulfated gastrin 17 and non-sulfated gastrin 17 (as exemplified in, inter alia, SEQ ID NO: 57 and SEQ ID NO: 60, respectively). Accordingly, said in vitro immunoassay detects and / or quantifies sulfated gastrin 17 with about 91.6% to about 110% sensitivity as compared to non-sulfated gastrin 17, when about 1 pmol / L to about 10 pmol / L nonsulfated gastrin 17 or sulfated gastrin 17 are supplied to said in vitro immunoassay, preferably wherein said non-sulfated gastrin 17 comprises an amino acid sequence as defined in SEQ IDs NO: 60 and sulfated gastrin 17 comprises an amino acid sequences as defined in SEQ IDs NO: 57. In this context, the values are preferably obtained by a method as exemplified in enclosed Example 9 using analytes (i.e., sulfated or non-sulfated gastrin 17) of up to 100 pmol / L.

[0285] As detailed herein above, the herein provided in vitro immunoassay comprises various advantageous characteristics. Said characteristics are, as is illustratively shown in the enclosed Example 11, advantageous over commercially available state of the art immunoassays as provided by Biohit or Snibe. Said advantageous characteristics comprise, inter alia, a lower limit of blank, a lower limit of detection, a lower limit of quantification, and a lower minimal sample volume as compared to the competitor immunoassays of Biohit and Snibe. Accordingly, said in vitro immunoassay comprises a limit of blank (LoB) of about 0.3 pmol / L or lower.

[0286] Accordingly, said in vitro immunoassay comprises a limit of detection (LoD) of about 0.5 pmol / L or lower.

[0287] Accordingly, said in vitro immunoassay comprises a limit of quantification (LoQ) at 20% CV of about 0.5 pmol / L or lower.

[0288] The quantification of LoB, LoD, and LoQ values may depend on the mass concentration of the employed calibrator. Accordingly, in the context of the present invention LoB, LoD, and LoQ values are preferably determined using gastrin 17 (as exemplified in SEQ ID NO: 59 or 60) as calibrator.

[0289] Accordingly, said in vitro immunoassay requires about or less than about 30 pL sample volume.

[0290] Further, said in vitro immunoassay comprises a within run coefficient of variation of about 1.4% or lower as evaluated using samples having gastrin-17 concentrations between 1.12 pmol / L and 73.1 pmol / L.

[0291] As mentioned herein above, the present invention, inter alia, also provides for diagnostic methods that employ the herein provided innovative antibodies. Accordingly, the present invention also provides for an in vitro immunoassay method for the detection and / or for the quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), wherein the method comprises the steps of: a) contacting a sample of a subject with the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and / or the above detailed monoclonal antibody binding to the N- terminus of gastrin 17; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s). In one aspect, the present invention also provides for an in vitro immunoassay method for the detection and / or for the quantification of gastrin 17, wherein the method comprises the steps of: a) contacting a sample of a subject with the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 and optionally with an antibody binding to the C-terminus of gastrin 17, preferably the above detailed monoclonal antibody binding to the C-terminus of gastrin 17; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to gastrin 17.

[0292] Preferably the present invention also provides for an in vitro immunoassay method for the detection and / or for the quantification of amidated gastrin 17, wherein the method comprises the steps of: a) contacting a sample of a subject with the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and an antibody specifically binding to gastrin 17, preferably an antibody specifically binding to the N-terminus of gastrin 17, more preferably the above detailed monoclonal antibody binding to the N-terminus of gastrin 17; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to amidated gastrin 17.

[0293] The sample may be a body fluid sample. In the context of the present invention, body fluid samples may be samples comprising one or more body fluids or modified body fluids (this means, inter alia, body fluids that have been concentrated, diluted, buffered, frozen, thawed, and the like). Body fluids may be derived from any animal that could benefit from the detection and / or quantification of one or more gastrin(s) and / or one or more cholecystokinin(s) (e.g., amidated G17) in their body fluids. Preferably, body fluids are derived from humans. Body fluids may be selected from the group consisting of the following: blood, cerebrospinal fluid, seminal fluid, saliva, urine, bile, feces, interstitial fluid. Preferably said body fluid sample is a blood sample. In the context of the present invention, a blood sample may be a serum sample, a plasma sample, or a whole blood sample, preferably a plasma sample or a serum sample.

[0294] Preferably at least one of said one or more monoclonal antibodies further comprises a detection label, preferably wherein said detection label is selected from the group consisting of an enzyme, a label emitting light, a label emitting radioactivity and / or a label absorbing light. Preferably the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s)is quantified by detecting and / or quantifying the amount of said one or more antibodies bound to said one or more gastrin(s) and / or said one or more cholecystokinin(s) via said detection label.

[0295] In a preferred embodiment of the above detailed method, said in vitro immunoassay comprises the detection and / or quantification of said gastrin with the above detailed monoclonal antibody binding to the C-terminus of gastrin 17, and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17. As is detailed herein above and below, when employing the herein above detailed monoclonal antibody binding to the C-terminus of gastrin 17 and the herein above detailed monoclonal antibody binding to the N-terminus of gastrin 17, the gastrin to be detected and / or quantified is amidated gastrin 17.

[0296] In a further preferred embodiment of the above detailed method, the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is a detection antibody and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17 is a capture antibody or wherein the above detailed monoclonal antibody binding to the C-terminus of gastrin 17 is a capture antibody and the above detailed monoclonal antibody binding to the N-terminus of gastrin 17is a detection antibody.

[0297] In another embodiment of the above detailed method, the in vitro immunoassay is a heterogeneous immunoassay.

[0298] The in vitro immunoassay may be a sandwich immunoassay.

[0299] As has been detailed herein above the herein provided monoclonal antibodies binding to the C- terminus of gastrin 17 or to the N-terminus of gastrin 17 are particularly useful for the detection of gastrin 17. As is evident from the enclosed examples, the herein provided monoclonal antibody binding to the N-terminus of gastrin 17 is sufficient to discriminate gastrin 17 (comprising an N- terminal pyroglutamate residue, as exemplified, inter alia, in SEQ ID NO: 60) from e.g., gastrin 13, gastrin 34, or CCK33. Accordingly, in a preferred embodiment of the above detailed method, the in vitro immunoassay specifically detects and / or specifically quantifies gastrin 17 using at least the herein above provided monoclonal antibody binding to the N-terminus of gastrin 17 and preferably using the herein above provided monoclonal antibody binding to the C-terminus of gastrin 17. Accordingly, said in vitro immunoassay does not detect CCK33 or any precursor thereof or any cleavage product thereof.

[0300] Accordingly, said in vitro immunoassay does not detect gastrin 34 or any precursor thereof or any cleavage product thereof, except for amidated G17.

[0301] Accordingly, said in vitro immunoassay does not detect gastrin 13.

[0302] As also detailed herein above, the herein provided monoclonal antibodies binding to the C- terminus of gastrin 17, specifically bind to the C-terminus of C-terminally amidated gastrin 17 (as exemplified, inter alia, in SEQ ID NO: 60). Accordingly, in another embodiment of the above detailed method, the in vitro immunoassay specifically detects and / or specifically quantifies amidated gastrin 17 using the herein above provided monoclonal antibody binding to the N- terminus of gastrin 17 and using the herein above provided monoclonal antibody binding to the C- terminus of gastrin 17.

[0303] Accordingly, in a further embodiment of the above detailed method, said in vitro immunoassay specifically detects and / or quantifies amidated gastrin 17 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 56 to 58 and 60.

[0304] As detailed herein above and as illustratively demonstrated, inter alia, in the enclosed Example 9, the herein provided monoclonal antibodies binding to the C-terminus of gastrin 17 (e.g., 9G1 and / or 7G7) can detect both sulfated gastrin 17 and non-sulfated gastrin 17 (as exemplified in, inter alia, SEQ ID NO: 57 and SEQ ID NO: 60, respectively). Accordingly, said in vitro immunoassay detects and / or quantifies sulfated gastrin 17 with about 91.6% to about 110% sensitivity as compared to non-sulfated gastrin 17, when about 1 pmol / L to about 10 pmol / L nonsulfated gastrin 17 or sulfated gastrin 17 are supplied to said in vitro immunoassay, preferably wherein said non-sulfated gastrin 17 comprises an amino acid sequence as defined in SEQ IDs NO: 60 and sulfated gastrin 17 comprises an amino acid sequences as defined in SEQ IDs NO: 57. In this context, the values are preferably obtained by a method as exemplified in enclosed Example 9 using analytes (i.e., sulfated or non-sulfated gastrin 17) of up to 100 pmol / L.

[0305] As detailed herein above, the herein provided in vitro immunoassay comprises various advantageous characteristics. Said characteristics are, as is illustratively shown in the enclosed Example 11, advantageous over commercially available state of the art immunoassays as provided by Biohit or Snibe. Said advantageous characteristics comprise, inter alia, a lower limit of blank, a lower limit of detection, a lower limit of quantification, and a lower minimal sample volume as compared to the competitor immunoassays of Biohit and Snibe.

[0306] Accordingly, said in vitro immunoassay comprises a limit of blank (LoB) of about 0.3 pmol / L or lower.

[0307] Accordingly, said in vitro immunoassay comprises a limit of detection (LoD) of about 0.5 pmol / L or lower.

[0308] Accordingly, said in vitro immunoassay comprises a limit of quantification (LoQ) at 20% CV of about 0.5 pmol / L or lower.

[0309] The quantification of LoB, LoD, and LoQ values may depend on the mass concentration of the employed calibrator. Accordingly, in the context of the present invention LoB, LoD, and LoQ values are preferably determined using gastrin 17 (as exemplified in SEQ ID NO: 59 or 60) as calibrator.

[0310] Accordingly, said in vitro immunoassay requires about or less than about 30 pL sample volume.

[0311] Further, said in vitro immunoassay comprises a within run coefficient of variation of about 1.4% or lower as evaluated using samples having gastrin-17 concentrations between 1.12 pmol / L and 73.1 pmol / L.

[0312] Table 1: Herein disclosed, non-limiting amino acid sequences. All sequences disclosed in Table 1 are further disclosed as part of the enclosed sequence listing. If not indicated differently, all sequences are amino acid sequences in the single letter code and from N-terminal (“N-ter”) to C-terminal (“C- ter”) orientation, whereas certain modification and / or features are described by non-standard identifiers further detailed in the Abbreviations sections below Table 2. “Full Seq” refers to the full-length sequence of the respective antibody chain. In this context, “H” indicates the heavy chain and “L” the light chain.

[0313]

[0314]

[0315]

[0316] The invention is also described by the following illustrative and non-limiting figures. The appended figures show:

[0317] Figure 1: Algorithm on how the plasma levels of stomach biomarkers are linked with non-atrophic Helicobacter pylori gastritis (previously so-called superficial gastritis) and with atrophic gastritis of various topographic phenotypes. Abbreviations: N = stomach mucosa is healthy; Hp = H. pylori, PGI = plasma pepsinogen I (pepsinogens I / II); G-17 = plasma G17 amidated. Figure 1 is derived from Agreus (2012) Scand J Gastroenterol 47(12), 1525, published as a correction to Agreus, L. (2012) Scandinavian journal of gastroenterology 47(2), 136-147.

[0318] Figure 2: Important posttranslational modifications of G17. Shown is the amino acid sequence of preprogastrin (see, inter alia, Copps (2009) Protein Pept Lett. 16(12), 1504-18). The black underscore highlights the amino acid sequence of gastrin 34 (G34) and the gastrin 17 (G17) amino acid sequence is highlighted in light grey and light grey underscore. Four possible posttranslational modifications that may naturally occur in G17 are highlighted by rectangles and are numbered from 1 to 4. These numbers highlight the following posttranslational modifications: 1. Glu at the G17 N-terminus converts to pyroglutamate; 2. Sulfation of Tyr87; 3. Met90 might be oxidized.; 4. Amidation of the G17 C-terminus.

[0319] Figure 3: G17 peptide derived immunogens. Based on the amino acid sequence of G17, anN-terminal and a C-terminal immunogen were designed (SEQ ID NO: 68 and SEQ ID NO: 74, respectively) and independently used for the immunization of rabbits in order to obtain an N-terminus- and a C-terminus specific antibody for G17, respectively. Abbreviations: Pyr = pyroglutamate; KLH = keyhole limpet hemocyanin; NH2 = C-terminal amidation N-terminal antigen

[0320] Figure 4: Kinetic Screening with exemplary kinetic signatures of antibodies binding to G17, other gastrin associated peptides, or CCK33. Depending on the immunogen, mAbs were screened for binding to different selections of analytes and cross reactants: GAST(83-92)-Bi (A01), sulfo- GAST(83-92)-Bi (A02), GAST(76-92)-Bi(A03), CCK33 (A04 & A09), GAST(83-93)amid-Bi (A05), GAST(83-91)-Bi (A06), GAST(76-92)-Bi (A07), GAST(59-92)-Bi (A08). A selection of Abs with recommended kinetic binding properties, B selection of sensorgrams representing deselected Abs after Screening. Figure 5: Kinetic profiles for antibody clones 9G1 (C-terminal binder), 41G5 (N-terminal binder) & 7G7 (alternative C-terminal binder) binding G17 associated analytes at 37 °C. Mass Transport corrected Langmuir 1:1 Fits are shown in gray and sensorgrams are shown in black. The kinetic quantification was facilitated with sufficiently high precision by using a 1 : 1 Langmuir binding model with the calculated maximal binding level (RMAX) set to global for each dilution series. A) Kinetic characterization of 9G1 and 41G5 against various G17 associated analytes. The G17 associated analytes are highlighted in each figure panel. The G17 and CCK33 dilution series ranged from 0.5 nM to 60 nM and were measured in duplicates. The remaining analyte dilution series either ranged from 1.2 nM to 120 nM for GAST(83-92)-Met(O)-Bi or from 1.2 to 900 nM for GAST(83-92)-Bi, GAST(83-93)-Bi & GAST(83-93)amid-Bi and were only measured once. B) Kinetic characterization of antibody 7G7, an alternative to 9G1, against different G17 associated peptides. Analyte dilution series ranged from 1.2 nM to up to 120 nM for G17, sulfo-G17, G34 & GAST(83-92)-Met(O)-Bi and from 1.2 to 900 nM for GAST(83-92)-Bi, GAST(83-93)-Bi & GAST(83-93)amid-Bi. For CCK33 dilution series ranged from 100 nM to 900 nM.

[0321] Figure 6. Crystal structures of 41G5 and 9G1 antibodies bound to the G17 ligand. Pictured are the variable regions of the two Fab structures rendered in cartoon, showing the heavy chain in cyan and the light chain in magenta. The ligand is rendered as a stick model with atomic coloring where carbon is shown in green, oxygen in red and nitrogen in blue.

[0322] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0323] The terms “amidated” and “C-terminally amidated” can herein be used interchangeably and in the context of the present invention refer to (poly)peptides comprising a C-terminal amino acid residue (i.e., a C-terminal phenylalanine residue) carrying an amid group. Accordingly, amidated gastrin 17 (as exemplified in e.g., SEQ ID NO: 60) comprises an am...

Claims

CLAIMS1. A monoclonal antibody specifically binding to an epitope consisting of an amino acid sequence of GWMDF (SEQ ID NO: 98); wherein F in position 5 in SEQ ID NO: 98 is C-terminally amidated, and wherein the sulfur atom comprised in the sulfide group of M in position 3 in SEQ ID NO: 98 may be oxidized, wherein said monoclonal antibody comprises: a) a heavy chain variable domain (VH) comprising Y in position 35 A; W in position 47; T in position 50; G in position 52; A in position 53; T in position 54; Y in position 58; V in position 97; S in position 99; V in position 100A; and Q in position 100B; and b) a light chain variable domain (VL) comprising Y in position 28; Y or W in position 32; Y in position 91; V or D in position 95C; and F in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

2. The monoclonal antibody according to claim 1, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 24, or a variant of SEQ ID NO: 3 or SEQ ID NO: 24 with at least about 90% amino acid sequence identity to SEQ ID NO: 3 or SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, or a variant of SEQ ID NO: 4 with at least about 90% amino acid sequence identity to SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 25, or a variant of SEQ ID NO: 5 or SEQ ID NO: 25 with at least about 90% amino acid sequence identity to SEQ ID NO: 5 or SEQ ID NO: 25,d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 31, or a variant of SEQ ID NO: 13 or SEQ ID NO: 31 with at least about 90% amino acid sequence identity to SEQ ID NO: 13 or SEQ ID NO: 31, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence SEQ ID NO: 15, SEQ ID NO: 33, or a variant of SEQ ID NO: 15 or SEQ ID NO: 33 with at least about 90% amino acid sequence identity to SEQ ID NO: 15 or SEQ ID NO: 33.

3. The monoclonal antibody according to claims 1 or 2, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3 or a variant thereof with an amino acid substitution in position 5 of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5 or a variant thereof with an amino acid substitution in position 10 of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13 or a variant thereof with amino acid substitutions in one or more positions selected from positions 2, 4, 5, 9, 11, 12, and 13 of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14 or a variant thereof with amino acid substitutions in position 1 and / or 4 of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15 or a variant thereof with amino acid substitutions in position 8 and / or 10 of SEQ ID NO: 15.

4. The monoclonal antibody according to any one of claims 1 to 3, wherein said monoclonal antibody comprises an equilibrium dissociation constant (KD) of about or less than about 4.17 x IO'10M when contacted with a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ IDs NO: 97 to 98.

5. The monoclonal antibody according to any one of claims 1 to 4, wherein when contacting said monoclonal antibody to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 60 or to a polypeptide consisting of an amino acid sequence as defined in SEQ ID NO: 57, the KD differs by about or less than about 25%.

6. The monoclonal antibody according to any one of claims 1 to 2, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 13, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 15.

7. The monoclonal antibody according to any one of claims 1 to 2, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 31, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 32, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 33.

8. A monoclonal antibody specifically binding to gastrin 17 comprising an N-terminal pyroglutamate residue, wherein said monoclonal antibody comprises:a) a heavy chain variable domain (VH) comprising W in position 33; W in position 47; C in position 50; W in position 58; D in position 95; Y in position 96; and b) a light chain variable domain (VL) comprising Y in position 28; V in position 91; R in position 96, wherein the position of the amino acids in said VH and said VL are indicated according to the Kabat numbering scheme.

9. The monoclonal antibody according to claim 8, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 40, c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 48, e) a CDR-L2, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50 or a variant thereof with at least about 90% amino acid sequence identity to SEQ ID NO: 50.

10. The monoclonal antibody according to claim 8 or 9, wherein said monoclonal antibody comprises: a) a CDR-H1 comprising or consisting of the amino acid sequence of SEQ ID NO: 39, b) a CDR-H2 comprising or consisting of the amino acid sequence of SEQ ID NO: 40,c) a CDR-H3 comprising or consisting of the amino acid sequence of SEQ ID NO: 41, d) a CDR-L1 comprising or consisting of the amino acid sequence of SEQ ID NO: 48, e) a CDR-L2 comprising or consisting of the amino acid sequence of SEQ ID NO: 49, and f) a CDR-L3 comprising or consisting of the amino acid sequence of SEQ ID NO: 50.

11. An in vitro immunoassay method for the detection and / or for the quantification of one or more gastrin(s) and / or one or more cholecystokinin(s), wherein the method comprises the steps of: a) contacting a sample of a subj ect with the monoclonal antibody according to any one of claims 1 to 7 and / or the monoclonal antibody according to any one of claims 8 to 10; and b) detection and / or quantification of the binding of said one or more monoclonal antibodies to said one or more gastrin(s) and / or said one or more cholecystokinin(s).

12. The method according to claim 11, wherein said in vitro immunoassay comprises the detection and / or quantification of said gastrin with the monoclonal antibody according to any one of claims 1 to 7, and the monoclonal antibody according to any one of claims 8 to 10, wherein the in vitro immunoassay specifically detects and / or specifically quantifies amidated gastrin 17.

13. The method according to any one of claims 11 to 12, wherein said in vitro immunoassay detects and / or quantifies sulfated gastrin 17 with about 91.6% to about 110% sensitivity as compared to non-sulfated gastrin 17.

14. The method according to any one of claims 11 to 14, wherein said in vitro immunoassay comprises a limit of detection (LoD) of about 0.5 pmol / L or lower.

15. A kit comprising the monoclonal antibody according to any one of claims 1 to 7 and / or the monoclonal antibody according to any one of claim 8 to 10.

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