TMEM219 antibodies for medical use

Abstract

The present disclosure relates to antibodies or antigen binding fragments thereof that bind to TMEM219 receptor for use in the treatment and / or prevention of colorectal cancer and / or reduction of risk of developing colorectal cancer. Pharmaceutical compositions comprising said antibody for use in the treatment and / or prevention of colorectal cancer are also herein disclosed.

Description

The inventors found TMEM219 as a therapeutic target for reducing incidence and severity of colorectal cancer consequent to chronic inflammation, in particular colitis-associated colorectal cancer. Accordingly, an anti-TMEM219 antibody can be advantageously used for the prevention and / or treatment of colorectal cancer, and / or reducing risk of developing colorectal cancer, such as colitis-associated colorectal cancer (CAC), in patients with inflammatory bowel disease (IBD)These data suggest that treatment of IBD with an anti-TMEM219 antibody offers superior reduction in risk of developing CRC in patients with IBD, and therefore may be preferred as the initial treatment for IBD, such as Crohn’s disease and ulcerative colitis (UC), or may be advantageously deployed as second line (2L) treatment in patients with IBD, either in patients whose response to initial treatment has decreased or in patients whose continue to respond to initial treatment but who are deemed at increased risk of developing CRC. For “colorectal cancer” or “CRC” is intended a cancer which begins in and / or affects at least a portion of the colon and / or of the rectum. The cancer can be at any stage, for example at stage 0, stage I, stage II, stage III or stage IV according to classifications known in the field. Colorectal cancer comprises colon cancer, bowel cancer, and rectal cancer. The cancer can also be a metastasis of another cancer. In an embodiment, the cancer is colitis-associated colorectal cancer. For “colitis-associated colorectal cancer” or “CAC” it is intended a type of colorectal cancer which is preceded by clinically detectable inflammatory bowel disease (IBD), such as Crohn's disease (CD) or Ulcerative colitis. “Tumor” and “cancer” are herein used as synonyms. For “prevention” is intended that administration of the agent decreases the chance or risk of developing a disease or condition, for example decreases the chance of developing a cancer, in particular a colorectal cancer. For “treatment” is intended that administration of the agent improves or cures or reverts a condition or a disease, i.e. it improves or cures or reverts a cancer. “Treatment” includes “reduction in progression” whereby administration of the agent slows down or stops progression of a disease that has already begun. For example, in some embodiments the agent disclosed is administered to a subject who already has cancer and, upon treatment as disclosed herein, the cancer does not develop to a more advanced stage. “Treatment” also encompasses that the disease, such as cancer, is not completely cured but reverts to a less advanced stage. Preferably, colorectal cancer is selected from the group consisting of colon cancer, bowel cancer, and rectal cancer. Preferably, colorectal cancer is colitis-associated colorectal (CAC) cancer. For “antibody that binds to TMEM219” is intended an antibody able to bind and / or block and / or neutralize, at least partially, TMEM219 receptor. Preferably it is an antibody that specifically binds TMEM219. TMEM219 is a known receptor of IGFBP3, an insulin-like growth factor binding protein. Anti-TMEM219 antibody or anti-TMEM antibody or antibody against TMEM219 or antibody that binds to TMEM219 are herein used as synonyms. By “antibody that specifically binds” TMEM219 is intended that the antibody will not substantially cross react with another, nonhomologous, human polypeptide. By “not substantially cross react” is intended that the antibody or fragment has a binding affinity for a non-homologous protein which is less than 10%, more preferably less than 5%, and even more preferably less than 1 %, of the binding affinity for TMEM219. In various embodiments, an antibody that "specifically binds" TMEM219, as used herein, includes antibodies that bind TMEM219 or the extracellular portion thereof, such as ecto-TMEM219, with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or about 0.5 nM, as measured with an Octet biolayer interferometry device or in a surface plasmon resonance assay, for example using the BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) or kinetic exclusion assays or any known method in the art. The term "antibody" herein is used in the broadest sense understood in the art, including all polypeptides described as antibodies. For example, the term “antibody”, as used herein, encompasses monoclonal antibodies, polyclonal antibodies, monospecific and multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as the fragment exhibits the desired antigen-binding activity (antigen-binding fragments). The term has its broadest art-recognized meaning and includes all known formats, including, without limitation: bivalent monospecific monoclonal antibodies, bivalent bispecific antibodies, trivalent trispecific antibodies, F(ab) fragments, F(ab)’2 fragments, scFv fragments, diabodies, single domain antibodies, including camelid VHH single domain antibodies, tandAbs, and flexibodies. The terms "antigen-binding fragment" of an antibody or equivalently "antigen-binding portion" of an antibody and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that comprises a portion of an antibody and that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc. As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. In particular embodiments, an antigen-binding fragment of an antibody comprises at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody include: (i) VH- CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may in various embodiments consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may in various embodiments comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)). The term “antigen-binding fragment” of an antibody further includes single domain antibodies. A single-domain antibody is an antibody fragment consisting of a single monomeric variable antibody domain. In some embodiments, the single-domain antibody is derived from the variable domain of the antibody heavy chain from camelids (also termed nanobodies, or VHH fragments). In some embodiments, the single-domain antibody is an autonomous human heavy chain variable domain (aVH) or VNAR fragments derived from sharks. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain- deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein. An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain. The antibody or binding molecule as herein disclosed can further be linked to an active substance, preferably a nanoparticle or a radionucleotide. As used herein, the term "antigen binding molecule" refers in its broadest sense to a molecule that specifically binds an antigenic determinant. Examples of antigen binding molecules are antibodies, including antigen-binding antibody fragments, and scaffold antigen binding proteins. The term "antigen binding moiety" refers to the portion of an antigen binding molecule that specifically binds to an antigenic determinant. Antigen binding moieties include antibodies and antigen-binding fragments thereof, such as scFv, that are capable of specific binding to an antigen on a target cell. In a particular aspect, the antigen binding moiety is able to direct the entity to which it is attached, such as a cell, to a target site. Anti-TMEM219 antibodies are known in the field. For example, anti-TMEM219 antibodies are described in WO2021094620. Preferred anti-TMEM219 antibodies for the use as herein disclosed are TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as disclosed in WO2021094620 and herein in Tables 1 -8, or encoded by the nucleotide sequences in Tables 9-10. A preferred anti-TMEM219 antibody is TC01, also herein named as EntOOI. In a preferred embodiment, said anti-TMEM219 antibody for the use as herein disclosed is TC01 and it comprises a light chain comprising a light variable region comprising or consisting of a sequence of SEQ ID NO. 39 and a light constant region comprising or consisting of a sequence of SEQ ID NO. 123 and / or a heavy chain comprising a heavy variable region comprising or consisting of a sequence of SEQ ID NO. 33 and a heavy constant region comprising or consisting of a sequence of SEQ ID NO. 120 or of SEQ ID NO. 180. The terms “region” and “domain” are herein used as synonyms. In a particular embodiment, said anti-TMEM219 antibody is TC01, and it comprises at least: a light chain comprising or consisting of the following sequence: QAVLTQPPSVSVSPGQTASITCSGDKLGNKNAYWYQQKPGQSPVLVMYQSTRRPS GIPERFSASNSGNTATLTISGTQAMDEADYYCQAWDSSSGWEVFGGGTKLTVLGQP KAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO. 4) and / or a heavy chain comprising or consisting of the following sequence: QIQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNG NTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARWGRWLAHDYWGQG TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO. 125) or of the following sequence: QIQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNG NTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARWGRWLAHDYWGQG TLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO. 126) In an embodiment, the anti-TMEM219 antibody molecule comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8 or encoded by the nucleotide sequences in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. In yet another embodiment, the anti-TMEM219 antibody molecule comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 18 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. In yet another embodiment, the anti-TMEM219 antibody molecule comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 18 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. In yet another embodiment, the anti-TMEM219 antibody molecule comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody chosen from any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 18 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. In yet another embodiment, the anti-TMEM219 antibody molecule includes a heavy chain constant region for an lgG4, e.g., a human lgG4. In one embodiment, the human lgG4 includes a substitution at position 228 (e.g., a Ser to Pro substitution). In one embodiment, the human lgG4 includes a substitution at position 235 (e.g., a Leu to Glu substitution). In one embodiment, the human lgG4 includes a substitution at position 228 (e.g., a Ser to Pro substitution) and a substitution at position 235 (e.g., a Leu to Glu substitution). In still another embodiment, the anti-TMEM219 antibody molecule includes a heavy chain constant region for an IgG 1, e.g., a human IgG 1. In one embodiment, the human lgG1 includes a substitution at position 297 (e.g., an Asn to Ala substitution). In one embodiment the human lgG1 includes a substitution at position 250, a substitution at position 428, or both (e.g., a Thr to Gin substitution at position 250 and / or a Met to Leu substitution at position 428). In one embodiment, the human lgG1 includes a substitution at position 234, a substitution at position 235, or both (e.g., a Leu to Ala substitution at position 234 and / or a Leu to Ala substitution at position 235). In yet another embodiment, the anti-TMEM219 antibody molecule includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In one embodiment, the light chain constant region comprises an amino sequence set forth in Table 11, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto. In another embodiment, the anti-TMEM219 antibody molecule includes a heavy chain constant region for an lgG4, e.g., a human lgG4, and a kappa light chain constant region, e.g., a human kappa light chain constant region. In one embodiment, the human lgG1 or lgG4 includes a substitution at the variable region to decrease aggregation, reduce charge heterogeneity, increase affinity and modulate antigen binding; removal by mutation of instability hotspot in the CDR, putative N-glycosylation sites in the variable region as described in (27), incorporated by reference. In one embodiment, the heavy chain constant region comprises an amino sequence set forth in Table 11, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto. In another embodiment, the anti-TMEM219 antibody molecule includes a heavy chain variable domain and a constant region, a light chain variable domain and a constant region, or both, comprising the amino acid sequence of any of TC01, TC03, TC04, TC05, TA02, TC01, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8, 11 or encoded by the nucleotide sequences in Tables 910; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. The anti-TMEM219 antibody molecule, optionally, comprises a leader sequence from a heavy chain, a light chain, or both. In yet another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1 -8 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. In yet another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Tables 1-8 or encoded by a nucleotide sequence shown in Tables 9-10. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-8 or encoded by a nucleotide sequence shown in Tables 9-10. In yet another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, or three CDRs from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequence. In yet another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, or three CDRs (or collectively all the CDRs) from a light chain variable region comprising an amino acid sequence shown in Tables 1-8 or encoded by a nucleotide sequence shown in Tables 9-10. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-8, or encoded by a nucleotide sequence shown in Tables 9-10. In certain embodiments, the anti-TMEM219 antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and / or CDR3 of the light chain. In another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Tables 1-8 or encoded by a nucleotide sequence shown in Tables 9-10. In one embodiment, one or more of the CDRs (or collectively all the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-8, or encoded by a nucleotide sequence shown in Tables 9-10. In one embodiment, the anti-TMEM219 antibody molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8, or encoded by the nucleotide sequences in Tables 9-10, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). In one embodiment, the anti-TMEM219 antibody molecule may include any CDR described herein. In certain embodiments, the anti-TMEM219 antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and / or CDR3 of the light chain. In another embodiment, the anti-TMEM219 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Tables 3, 5, 6) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Tables 3, 5, 6. The assignment of amino acids to each VL and VH domain is in accordance with any conventional definition of CDRs. The CDRs of the present disclosure have been annotated with abYsis annotation tool from http: / / www.abysis.org / , using the Kabat, Chothia, AbM (Martin), Contact and IMGT numbering schemes. Those skilled in the art of antibodies will appreciate that these conventions consist of nonsequential numbering in specific regions of an immunoglobulin sequence, enabling a normalized reference to conserved positions in immunoglobulin families. Accordingly, the positions of any given immunoglobulin as defined by Kabat or Chothia or AbM (Martin) or Contact or IMGT numbering will not necessarily correspond to its sequential sequence. Conventional definitions include, the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991), the Chothia definition (Chothia & Lesk, J. Mol. Biol. 196: 901-917, 1987; Chothia et al., Nature 342: 878-883, 1989); the AbM definition used by Oxford Molecular’s antibody modelling software; and, the Contact definition of Martin et al. (bioinfo.org. uk / abs); the IMGT definition (Lefranc, M.-P. and Lefranc, G. The Immunoglobulin FactsBook Academic Press, London, UK (2001); Lefranc, M.-P. and Lefranc, G. TheT cell receptor FactsBook Academic Press, London, UK (2001)); the Eu numbering system, also referred herein, relates to the sequence numbering used in the description of the human IgGI myeloma protein called Eu (Edelman GM et al., Proc Natl Acad Sci USA 63(1):78-85, 1969). Thus, in any immunoglobulin molecule such as an antibody or fragment thereof or an antibody-like molecule, then amino acid in a given position number relates to, or corresponds to, the corresponding amino acid residue position number in the Eu sequence. Kabat provides a widely used numbering convention (Kabat numbering system) in which corresponding residues between different heavy chains or between different light chains are assigned the same number. The present disclosure can use CDRs defined according to any of these numbering systems, although preferred embodiments use Kabat defined CDRs. In one embodiment, the anti-TMEM219 antibody molecule comprises: (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from any one of SEQ ID NO: 1, 8, 10, 56, 59, 62, 65 and 68; a VHCDR2 amino acid sequence chosen from any one of SEQ ID NO: 2, 5, 11,57, 60, 63, 66 and 69; and a VHCDR3 amino acid sequence chosen from any one of SEQ ID NO: 3, 6, 7, 9, 12, 13, 58, 61, 64, 67 and 70; and (ii) a light chain variable region (VL) comprising a VLCDR1 amino acid sequence chosen from any one of SEQ ID NO: 14, 17, 20, 23, 26, 29, 71, 77, 80, 82 and 85, a VLCDR2 amino acid sequence chosen from any one of SEQ ID NO: 15, 18, 21, 24, 27, 30, 72, 78, 83 and 86, and a VLCDR3 amino acid sequence chosen from SEQ ID NO: 16, 19, 22, 25, 28, 31, 73, 74, 75, 76, 79, 81, 84 and 87. In one embodiment, the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TMEM219 antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or preferably 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In one embodiment, the light or heavy chain variable framework region (particularly FR1, FR2 and / or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germ line gene. In certain embodiments, the anti-TMEM219 antibody molecule comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions. In one embodiment, the heavy or light chain variable region, or both, of the anti-TMEM219 antibody molecule includes an amino acid sequence encoded by a nucleic acid sequence described herein or a nucleic acid that hybridizes to a nucleic acid sequence described herein (e.g., a nucleic acid sequence as shown in Tables 9-10) or its complement, e.g., under low stringency, medium stringency, or high stringency, or other hybridization conditions described herein. In another embodiment, the anti-TMEM219 antibody molecule comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Tables 7-8 or a sequence substantially identical thereto, e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Tables 7-8. In another embodiment, the anti-TMEM219 antibody molecule includes a VH and / or a VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Tables 9-10 or a sequence substantially identical thereto, e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 9-10. In yet other embodiments, the anti-TMEM219 antibody molecule has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgG 1, lgG2, lgG3, lgG4, IgM, lgA1, lgA2, IgD, and IgE; particularly, chosen from, e.g., the heavy chain constant regions of lgG1, lgG2, lgG3, and lgG4, more particularly, the heavy chain constant region of lgG1 or lgG4 (e.g., human lgG1, lgG2 or lgG4). In one embodiment, the heavy chain constant region is human lgG1. In another embodiment, the anti-TMEM219 antibody molecule has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda. In one embodiment, the constant region is altered, e.g., mutated, to modify the properties of the anti-TMEM219 antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, complement function, half-life, aggregation and stability). In certain embodiments, the anti-TMEM antibody molecules comprise a human lgG4 mutated. The constant region of an antibody is important in the ability of an antibody to fix complement and mediate celldependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity. In certain embodiments, the constant region is an lgG1, lgG2, lgG3, lgG4 constant region. In one embodiment, the anti-TMEM219 antibody molecule is isolated or recombinant. In one embodiment, the anti-TMEM219 antibody molecule is a humanized or human antibody molecule. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies may in various embodiments nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in some embodiments, CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences are derived from the germline of another mammalian species, such as a mouse, which have been grafted onto human framework sequences. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.20:6287-6295, incorporated herein by reference in its entirety,) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. An "isolated antibody," as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody." In various embodiments, the isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals. The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen. The disclosure also features a nucleic acid molecule that comprises one or both nucleotide sequences that encode heavy and light chain variable regions, CDRs, hypervariable loops, framework regions of the anti-TMEM219 antibody molecules, as described herein, for use for the prevention and / or treatment of colorectal cancer. In certain embodiments, the nucleotide sequence that encodes the anti-TMEM219 antibody molecule is codon optimized. For example, a first and second nucleic acids encoding heavy and light chain variable regions, respectively, of an anti-TMEM219 antibody molecule chosen from one or more of, e.g., any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8 or encoded by the nucleotide sequence in Tables 9-10, or a sequence substantially identical thereto can be used. For example, the nucleic acid can comprise a nucleotide sequence as set forth in Tables 9-10, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 9-10). In other embodiments, the nucleic acid molecule comprises a nucleotide sequence that encodes a heavy chain variable domain and / or a heavy chain constant region comprising the amino acid sequence of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 1-8 or encoded by the nucleotide sequence in Tables 9-10; or a sequence substantially identical (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the aforesaid sequences. In other embodiments, the nucleic acid molecule comprises a nucleotide sequence that encodes a light chain variable domain and / or a light chain constant region comprising the amino acid sequence of any of TC01, TC03, TC04, TC05, TA02, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 18 or the nucleotide sequence in Tables 9-10, or a sequence substantially identical (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the aforesaid sequences. The aforesaid nucleotide sequences encoding the anti-TMEM219 heavy and light chain variable domain and constant regions can be present in a separate nucleic acid molecule, or in the same nucleic acid molecule. In certain embodiments, the nucleic acid molecules comprise a nucleotide sequence encoding a leader sequence. In certain embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two, or three CDRs, or hypervariable loops, from a heavy chain variable region having an amino acid sequence as set forth in Tables 1-8, ora sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). In another embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two, or three CDRs, or hypervariable loops, from a light chain variable region having an amino acid sequence as set forth in Tables 1-8 or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). In yet another embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs, or hypervariable loops, from heavy and light chain variable regions having an amino acid sequence as set forth in Tables 1-8 or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). In another embodiment, the nucleic acid molecule includes one or more heavy chain framework region (e.g., any of VHFW1 (type a), VHFW1 (type b), VHFW1 (type c), VHFW1 (type d), VHFW2 (type a), VHFW2 (type a'), VHFW2 (type b), VHFW2 (type c), VHFW2 (type d), VHFW2 (type e), VHFW3 (type a), VHFW3 (type b), VHFW3 (type c), VHFW3 (type d), VHFW3 (type e), or VHFW4, or any combination thereof, e.g., a framework combination as described herein) for any of TA02, TC01, TC02, TD01, TE01, TG02, TM1, TE02.1, TE02.2, TE02.3, TE03, TE04, TE07, TE10 as defined in Tables 18, or a sequence substantially identical thereto. For example, the nucleic acid molecule can comprise a nucleotide sequence as set forth in Tables 9-10, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 9-10). In another embodiment, the nucleic acid molecule includes one or more light chain framework region (e.g., any of VLFW1 (type a), VLFW1 (type b), VLFW1 (type c), VLFW1 (type d), VLFW1 (type e), VLFW1 (type f), VLFW2 (type a), VLFW2 (type c), VLFW3 (type a), VLFW3 (type b), VLFW3 (type c), VLFW3 (type d), VLFW3 (type e), VLFW3 (type f), VLFW3 (type g), or VLFW4, or any combination thereof, e.g., a framework combination as described herein) for of any of E01, E02, E08, E14, E19, E20, E23, E24 or M1 as defined in Tables 1-8, or a sequence substantially identical thereto. For example, the nucleic acid molecule can comprise a nucleotide sequence as set forth in Tables 9-10, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 9-10). In another embodiment, the nucleic acid molecule includes one or more heavy chain framework region and one or more light chain framework region as described herein. The heavy and light chain framework regions may be present in the same vector or separate vectors. Host cells and vectors containing the nucleic acids described herein or modified for codon optimization according to known methods can also be used. The nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell. The host cell can be a eukaryotic cell, e.g., a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, e.g., E. coli. For example, the mammalian cell can be a cultured cell or a cell line. Exemplary mammalian cells include lymphocytic cell lines (e.g., NSO), Chinese hamster ovary cells (CHO), COS cells, oocyte cells, and cells from a transgenic animal, e.g., mammary epithelial cell. In another aspect, the disclosure provides, compositions, e.g., pharmaceutical compositions, for use for the prevention and / or treatment of colorectal cancer which include a pharmaceutically acceptable carrier, excipient or stabilizer, and at least one anti-TMEM219 antibody, such as the ones described herein. Preferably said pharmaceutical composition includes anti-TMEM219 antibody TC01, as described herein. In one embodiment, the composition, e.g., the pharmaceutical composition, includes a combination of the antibody molecule and one or more agents, e.g., an anticancer therapeutic agent or other anti-TMEM219 antibody molecule, as described herein. In one embodiment, the antibody molecule is conjugated to a label or a therapeutic agent. The present disclosure also includes anti-TMEM219 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. The antibody can be administered to the subject in various embodiments in a formulation comprising suitable carriers, excipients, and other agents to provide improved transfer, delivery, tolerance, and the like, and suitable for an intravenous or subcutaneous injection. The injectable preparations may be prepared by methods publicly known. For example, injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 20 or 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injectable preparation thus prepared can be filled in an appropriate ampoule. The antibody for the use as herein disclosed can be administered to the subject using any acceptable device or mechanism. For example, the administration can be accomplished using a syringe and needle or with a reusable pen and / or autoinjector delivery device. The methods of the present disclosure include the use of numerous reusable pen and / or autoinjector delivery devices to administer an antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen and / or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), the HUMIRA™ Pen (Abbott Labs, Abbott Park, IL), the DAI® Auto Injector (SHL Group) and any auto-injector featuring the PUSHCLICK™ technology (SHL Group), to name only a few. In one embodiment, the antibody is administered with a prefilled syringe. In another embodiment, the antibody is administered with a prefilled syringe containing a safety system. For example, the safety system prevents an accidental needlestick injury. In various embodiments, the antibody is administered with a prefilled syringe containing an ERIS™ safety system (West Pharmaceutical Services Inc.). See also U.S. patent numbers 5,215,534 and 9,248,242, incorporated herein by reference in their entireties. In another embodiment, the antibody is administered with an auto-injector. In various embodiments, the antibody is administered with an auto-injector featuring the PUSHCLICK™ technology (SHL Group). In various embodiments, the auto-injector is a device comprising a syringe that allows for administration of a dose of the composition and / or antibody to a subject. See also U.S. patent numbers 9,427,531 and 9,566,395 3. According to the disclosure, “subject” means a human subject or human patient. In one embodiment, the subject is in need of inhibiting, reducing, neutralizing or blocking colorectal cancer. In one embodiment, the subject has, or is at risk of having, colorectal cancer. The content of the antibody or antigen binding fragment thereof in the pharmaceutical composition for the use as disclosed is not limited as far as it is useful for treatment or prevention of colorectal cancer but preferably contains 0.0000001-10% by weight per total composition. The choice of the carrier may depend upon the route of administration and concentration of the active agent(s) and the carrier may be in the form of a lyophilised composition or an aqueous solution. Generally, an appropriate amount of a pharmaceutically acceptable salt is used in the carrier to render the composition isotonic. Examples of the carrier include but are not limited to saline, Ringer's solution and dextrose solution. Preferably, acceptable excipients, carriers, or stabilizers are non-toxic at the dosages and concentrations employed, including buffers such as citrate, phosphate, and other organic acids; salt-forming counter- ions, e.g. sodium and potassium; low molecular weight (> 10 amino acid residues) polypeptides; proteins, e.g. serum albumin, or gelatine; hydrophilic polymers, e.g. polyvinylpyrrolidone; amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine; carbohydrates including glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars, e.g. sucrose, mannitol, trehalose or sorbitol; chelating agents, e.g. EDTA; non-ionic surfactants, e.g. Tween, Pluronics or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and / or preservatives, e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium 5 chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol). Suitable carriers and their formulations are described in greater detail in Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Co. The composition may also contain at least one further active compound, such as a chemotherapeutic agent. 10 Preferably, the antibody or antigen binding fragment thereof is included in a pharmaceutical composition for the use as herein disclosed in an effective amount. The term "effective amount" refers to an amount sufficient to induce a detectable therapeutic response in the subject to which the pharmaceutical composition is to be administered. 15 SEQUENCES Table 1: VH CDR Sequences Antibody CDR1 CDR2 CDR3 TC01 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) WGRWLAHDY (SEQ ID NO. 6) TC03 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) WGRWLAHDY (SEQ ID NO. 6) TC04 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) WGRWLAHDY (SEQ ID NO. 6) TC05 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) WGRWLAHDY (SEQ ID NO. 6) TA02 SYAIS (SEQ ID NO. 1) GIIPIFGTANYAQKF QG (SEQ ID NO. 2) GDIAAAGRKGLPIYY MDV (SEQ ID NO. 3) TC02 SYAIS (SEQ ID NO. 1) GIIPIFGTANYAQKF QG (SEQ ID NO. 2) PSGYYIYDAFDI (SEQ ID NO. 7) TD01 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) DLGWPDDY (SEQ ID NO. 9) TE01 DYGMS (SEQ ID NO. 10) GINWNGGSTGYAD SVKG (SEQ ID NO. 11) DRLRYCSSTSCYIP DY (SEQ ID NO. 12) WO 2025 / 215235 PCT / EP2025 / 060122 TG02 SYGIS (SEQ ID NO. 8) WISAYNGNTNYAQ KLQG (SEQ ID NO. 5) VGSTYDFWSGAYY YYGMDV (SEQ ID NO. 13) TE02.1 GFTFSRHG (SEQ ID NO. 56) IWYDGRNK (SEQ ID NO. 57) AREGITMVRGVIPLF DY (SEQ ID NO. 58) TE02.2 GFTFSRHG (SEQ ID NO. 56) IWYDGRNK (SEQ ID NO. 57) AREGITMVRGVIPLF DY (SEQ ID NO. 58) TE02.3 GFTFSRHG (SEQ ID NO. 56) IWYDGRNK (SEQ ID NO. 57) AREGITMVRGVIPLF DY (SEQ ID NO. 58) TE03 GFTFSRYG (SEQ ID NO. 59) IWYDGSYK (SEQ ID NO. 60) ARFGILTGYYFDY (SEQ ID NO. 61) TE04 GFTFSRHG (SEQ ID NO. 56) IWYDGRNK (SEQ ID NO. 57) AREGITMVRGVIPLF DY (SEQ ID NO. 58) TE07 GFTFSSYA (SEQ ID NO. 62) ISGSGYST (SEQ ID NO. 63) AKGKVGPTYAFDL (SEQ ID NO. 64) TE10 GFTFSSYG (SEQ ID NO. 65) IWYDGSNK (SEQ ID NO. 66) AREGRGMDV (SEQ ID NO. 67) TM1 GFTFSTYG (SEQ ID NO. 68) IWYDGYNK (SEQ ID NO. 69) EGWFGKLLSALDI (SEQ ID NO. 70) Table 2: VL CDR Sequences Antibody CDR1 CDR2 CDR3 TC01 SGDKLGNKNAY (SEQ ID NO. 17) QSTRRPS (SEQ ID NO. 18) QAWDSSSGWEV (SEQ ID NO. 19) TC03 SGDKLGNKNAY (SEQ ID NO. 17) QSTRRPS (SEQ ID NO. 18) QAWLSSSGWEV (SEQ ID NO. 166) TC04 SGDKLGNKNAY (SEQ ID NO. 17) QSTRRPS (SEQ ID NO. 18) QAWDSSSGWEV (SEQ ID NO. 19 TC05 SGDKLGNKNAY (SEQ ID NO. 17) QSTRRPS (SEQ ID NO. 18) QAWDSSSGWEV (SEQ ID NO. 19) TA02 QASQDISNYLN (SEQ ID NO. 14) AASSLQS (SEQ ID NO. 15) QQSYSTPT (SEQ ID NO. 16) TC02 GASQSVSSSYLA (SEQ ID NO. 20) DASSRAT (SEQ ID NO. 21) HQYNNWPRT (SEQ ID NO. 22) TD01 SGSSSNIGSNYVY (SEQ ID NO. 23) RNNQRPS (SEQ ID NO. 24) AAWDDSLNGVV (SEQ ID NO. 25) TE01 KSSQSVLDSSNNKNYVA WASTRES QQYYTTRWT (SEQ ID NO. 26) (SEQ ID NO. 27) (SEQ ID NO. 28) TG02 RASQGIRNDLG (SEQ ID NO. 29) DASNLET (SEQ ID NO. 30) QQYDNLPLT (SEQ ID NO. 31) TE02.1 SGHSSYA (SEQ ID NO. 71) LNSDGSH (SEQ ID NO. 72) QTWGTGMLC (SEQ ID NO. 73) TE02.2 SGHSSYA (SEQ ID NO. 71) LNSDGSH (SEQ ID NO. 72) QTWGTGMLF (SEQ ID NO. 74) TE02.3 SGHSSYA (SEQ ID NO. 71) LNSDGSH (SEQ ID NO. 72) QTWGTGMLW (SEQ ID NO. 75) TE03 SGHSSYA (SEQ ID NO. 71) LNSDGSH (SEQ ID NO. 72) QTWGTGCC (SEQ ID NO. 76) TE04 SGSVSTSYN (SEQ ID NO. 77) STN (SEQ ID NO. 78) VLYMGSGII (SEQ ID NO. 79) TE07 SGSVSTSYY (SEQ ID NO. 80) STN (SEQ ID NO. 78) VLYMGSGTCC (SEQ ID NO. 81) TE10 SGHSSYI (SEQ ID NO. 82) LEGSGSY (SEQ ID NO. 83) ETWDSNTPHAV (SEQ ID NO. 84) TM1 QGIRND (SEQ ID NO. 85) PAS (SEQ ID NO. 86) LQDYNYPFT (SEQ ID NO. 87) CDR definition is also provided using annotation tool from http: / / www.abysis.org / based on full VH and VL amino acid sequences as defined in Tables 7 and 8. Below is shown the example in reference to SEQ ID No. 33 (VH of TC01). Table 3: Kabat defined CDR sequences Region Sequence Fragment Residues HFR1 QIQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID No. 127) 1 -30 CDR-H1 SYGIS (SEQ ID No. 8) 31 -35 HFR2 WVRQAPGQGLEWMG (SEQ ID No. 128) 36-49 CDR-H2 WISAYNGNTNYAQKLQG (SEQ ID No. 5) 50-66 HFR3 RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID No. 129) 67-98 CDR-H3 WGRWLAHDY (SEQ ID No. 6) 99-107 HFR4 WGQGTLVTVSS (SEQ ID No. 130) 108-118 The VH amino acid sequence of any antibody may also be plugged into the annotation tool and IMGT defined CDR sequences are provided. 5 Below is shown the example in reference to SEQ ID No. 33 (VH of TC01). Table 4: IMGT defined CDR sequences Region Sequence Fragment Residues HFR1 QIQLVQSGAEVKKPGASVKVSCKAS (SEQ ID No. 131) 1 -25 CDR-H1 GYTFTSYG (SEQ ID No. 132) 26-33 HFR2 ISWVRQAPGQGLEWMGW (SEQ ID No. 133) 34-50 CDR-H2 ISAYNGNT (SEQ ID No. 134) 51 -58 HFR3 NYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYC (SEQ ID No. 135) 59-96 CDR-H3 ARWGRWLAHDY (SEQ ID No. 136) 97 -107 HFR4 WGQGTLVTVSS (SEQ ID No. 130) 108-118 10 In addition, the VH amino acid sequence of any antibody disclosed herein may also be plugged into the annotation tool and the “All, side by side” defined CDR sequences are provided. Below is shown the example in reference to SEQ ID No. 33 (VH of TC01). 15 Table 5: All, side by side defined CDR sequences Region Definition Sequence Fragment Residues HFR1 Chothia QIQLVQSGAEVKKPGASVKVSCKAS-----(SEQ ID No. 131) 1 -25 AbM QIQLVQSGAEVKKPGASVKVSCKAS-----(SEQ ID No. 131) 1 -25 Kabat QIQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID No. 127) 1 -30 Contact QIQLVQSGAEVKKPGASVKVSCKASGYTF-(SEQ ID No. 138) 1 -29 IMGT QIQLVQSGAEVKKPGASVKVSCKAS-----(SEQ ID No. 131) 1 -25 CDR- H1 Chothia GYTFTSY—(SEQ ID No. 139) 26-32 AbM GYTFTSYGIS (SEQ ID No. 140) 26-35 Kabat -----SYGIS (SEQ ID No. 8) 31 -35 Contact —TSYGIS (SEQ ID No. 141) 30-35 IMGT GYTFTSYG-(SEQ ID No. 132) 26-33 HFR2 Chothia GISWVRQAPGQGLEWMGWI (SEQ ID No. 142) 33-51 AbM —WVRQAPGQGLEWMG- (SEQ ID No. 128) 36-49 Kabat —WVRQAPGQGLEWMG-(SEQ ID No. 128) 36-49 Contact —WVRQAPGQGLE-----(SEQ ID No. 143) 36-46 IMGT -ISWVRQAPGQGLEWMGW-(SEQ ID No. 133) 34-50 CDR- H2 Chothia -----SAYNGN---------(SEQ ID No. 144) 52-57 AbM —WISAYNGNTN-------(SEQ ID No. 145) 50-59 Kabat —WISAYNGNTNYAQKLQG (SEQ ID No. 5) 50-66 Contact WMGWISAYNGNTN-------(SEQ ID No. 146) 47-59 IMGT —ISAYNGNT--------(SEQ ID No. 134) 51 -58 HFR3 Chothia TNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID No. 147) 58-98 AbM -YAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID No. 148) 60-98 Kabat ---------RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID No. 129) 67-98 Contact -YAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYC— (SEQ ID No. 149) 60-96 IMGT -NYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYC— (SEQ ID No. 135) 59-96 CDR- H3 Chothia -WGRWLAHDY (SEQ ID No. 6) 99-107 AbM -WGRWLAHDY (SEQ ID No. 6) 99-107 Kabat -WGRWLAHDY (SEQ ID No. 6) 99-107 Contact ARWGRWLAHD-(SEQ ID No. 150) 97 -106 IMGT ARWGRWLAHDY (SEQ ID No. 136) 97-107 HFR4 Chothia -WGQGTLVTVSS (SEQ ID No. 130) 108-118 AbM -WGQGTLVTVSS (SEQ ID No. 130) 108-118 Kabat -WGQGTLVTVSS (SEQ ID No. 130) 108-118 Contact YWGQGTLVTVSS (SEQ ID No. 151) 107-118 IMGT -WGQGTLVTVSS (SEQ ID No. 130) 108-118 CDR definition provided using annotation tool from http: / / www.abysis.org / based on full VL amino acid sequence of TC01 (SEQ ID No. 39) is also reported. Table 6: All, side by side defined CDR sequences Region Definition Sequence Fragment Residues LFR1 Chothia QAVLTQPPSVSVSPGQTASITC------(SEQ ID No. 152) 1 -22 AbM QAVLTQPPSVSVSPGQTASITC------(SEQ ID No. 152) 1 -22 Kabat QAVLTQPPSVSVSPGQTASITC------(SEQ ID No. 152) 1 -22 Contact QAVLTQPPSVSVSPGQTASITCSGDKLG (SEQ ID No. 153) 1 -28 IMGT QAVLTQPPSVSVSPGQTASITCSGD—(SEQ ID No. 154) 1 -25 CDR-L1 Chothia SGDKLGNKNAY-(SEQ ID No. 17) 23-33 AbM SGDKLGNKNAY-(SEQ ID No. 17) 23-33 Kabat SGDKLGNKNAY-(SEQ ID No. 17) 23-33 Contact ------NKNAYWY (SEQ ID No. 155) 29-35 IMGT —KLGNKN—(SEQ ID No. 156) 26-31 LFR2 Chothia -WYQQKPGQSPVLVMY (SEQ ID No. 156) 34-48 AbM -WYQQKPGQSPVLVMY (SEQ ID No. 156) 34-48 Kabat -WYQQKPGQSPVLVMY (SEQ ID No. 156) 34-48 Contact —QQKPGQSPV—(SEQ ID No. 157) 36-44 IMGT AYWYQQKPGQSPVLVMY (SEQ ID No. 158) 32-48 CDR-L2 Chothia —QSTRRPS (SEQ ID No. 18) 49-55 AbM —QSTRRPS (SEQ ID No. 18) 49-55 Kabat —QSTRRPS (SEQ ID No. 18) 49-55 Contact LVMYQSTRRP-(SEQ ID No. 159) 45-54 IMGT —-QS----- 49-50 LFR3 Chothia -----GIPERFSASNSGNTATLTISGTQAMDEADYYC (SEQ ID No. 160) 56-87 AbM -----GIPERFSASNSGNTATLTISGTQAMDEADYYC (SEQ ID No. 160) 56-87 Kabat -----GIPERFSASNSGNTATLTISGTQAMDEADYYC (SEQ ID No. 160) 56-87 Contact —SGIPERFSASNSGNTATLTISGTQAMDEADYYC (SEQ ID No. 161) 55-87 IMGT TRRPSGIPERFSASNSGNTATLTISGTQAMDEADYYC (SEQ ID No. 162) 51 -87 CDR-L3 Chothia QAWDSSSGWEV (SEQ ID No. 19) 88-98 AbM QAWDSSSGWEV (SEQ ID No. 19) 88-98 Kabat QAWDSSSGWEV (SEQ ID No. 19) 88-98 Contact QAWDSSSGWE- (SEQ ID No. 163) 88-97 IMGT QAWDSSSGWEV (SEQ ID No. 19) 88-98 LFR4 Chothia -FGGGTKLTVL (SEQ ID No. 164) 99-108 AbM -FGGGTKLTVL (SEQ ID No. 164) 99-108 Kabat -FGGGTKLTVL (SEQ ID No. 164) 99-108 Contact VFGGGTKLTVL (SEQ ID No. 165) 98-108 IMGT -FGGGTKLTVL (SEQ ID No. 164) 99-108 Table 7: VH amino acid sequences of exemplified antibodies Antibody AA of VH TC01 QIQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARW GRWLAHDYWGQGTLVTVSS (SEQ ID NO. 33) TC03 QIQLVQSGAEVKQPGASVSVSCAASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELSSLRSDDTAVYYCARW GRWLAHDYWGQGTLVTVSS (SEQ ID NO. 168) TC04 QIQLVQSGAEVKQPGASVSVSCAASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELSSLRSDDTAVYYCARW GRWLAHDYWGQGTLVTVSS (SEQ ID NO. 168) TC05 QIQLVQSGAEVKQPGASVSVSCAASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELSSLRSDDTAVYYCARW GRWLAHDYWGQGTLVTVSS (SEQ ID NO. 168) TA02 QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG GIIPIFGTANYAQKFQGRVTITADESTSTAYMELSNLRSEDTAVYYCARGDIA AAGRKGLPIYYMDVWGKGTTVTVSS (SEQ ID NO. 32) TC02 QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG GIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASPSGY YIYDAFDIWGQGTMVTVSS (SEQ ID NO. 34) TD01 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDL GWPDDYWGQGTLVTVSS (SEQ ID NO. 35) TE01 EVQLLESGGGWRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVS GINWNGGSTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAKDR LRYCSSTSCYIPDYWGQGTLVTVSS (SEQ ID NO. 36) TG02 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMG WISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARV GSTYDFWSGAYYYYGMDVWGQGTTVTVSS (SEQ ID NO. 37) TE02.1 QVQLVESGGGWQPGRSLRLSCAASGFTFSRHGMHWVRQAPGKGLEWVA VIWYDGRNKYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAREG ITMVRGVIPLFDYWGQGTLVTVSS (SEQ ID NO. 88) TE02.2 QVQLVESGGGWQPGRSLRLSCAASGFTFSRHGMHWVRQAPGKGLEWVA VIWYDGRNKYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAREG ITMVRGVIPLFDYWGQGTLVTVSS (SEQ ID NO. 88) TE02.3 QVQLVESGGGWQPGRSLRLSCAASGFTFSRHGMHWVRQAPGKGLEWVA VIWYDGRNKYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAREG ITMVRGVIPLFDYWGQGTLVTVSS (SEQ ID NO. 88) TE03 QVQLVESGGGWQPGRSLRLSCAASGFTFSRYGMHWVRQAPGKGLEWVA VIWYDGSYKYYADSIKGRFTVSRDNSKNTLYLQMNSLRAEDTALYYCARFGI LTGYYFDYWGQGTLVTVSS (SEQ ID NO. 91) TE04 QVQLVESGGGWQPGRSLRLSCAASGFTFSRHGMHWVRQAPGKGLEWVA VIWYDGRNKYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAREG ITMVRGVIPLFDYWGQGTLVTVSS (SEQ ID NO. 88) TE07 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGEGLEWVS GISGSGYSTYSADSVKGRFTIFKDNSKNTLYLQINSLRAEDTAVYYCAKGKV GPTYAFDLWGQGTMVTVSS (SEQ ID NO. 93) TE10 QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVA VIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREG RGMDVWGQGTTVTVSS (SEQ ID NO. 94) TM1 QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGIHWVRQAPGKGLEWVAV IWYDGYNKYYVDSVKGRFTISRDNSENTVYLQMNSLRTEDTAVYYCAREG WFGKLLSALDIWGQGTMVTVSS (SEQ ID NO. 95) Table 8: VL amino acid sequences of exemplified antibodies Antibody AA of VL TC01 QAVLTQPPSVSVSPGQTASITCSGDKLGNKNAYWYQQKPGQSPVLVM YQSTRRPSGIPERFSASNSGNTATLTISGTQAMDEADYYCQAWDSSS GWEVFGGGTKLTVL (SEQ ID NO. 39) TC03 QAVLTQPPSVSVSPGQTASITCSGDKLGNKNAYWYQQKPGQSPVLVM YQSTRRPSGIPERFSASNSGNTATLTISGTQAMDEADYYCQAWLSSS GWEVFGGGTKLTVL (SEQ ID NO. 171) TC04 QAVLTQPPSVSVSPGQTASITCSGDKLGNKNAYWYQQKPGQSPVLVM YQSTRRPSGIPERFSASNSGNTATLTISGTQAEDEADYYCQAWDSSS GWEVFGGGTKLTVL (SEQ ID NO. 172) TC05 QAVLTQPPSVSVSPGQTASITCSGDKLGNKNAYWYQQKPGQSPVLVM YQSTRRPSGIPERFSASNSGNTATLTISGTQAMDEADYYCQAWDSSS GWEVFGGGTKLTVL (SEQ ID NO. 39) TA02 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIY AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPTF GQGTKLEIK (SEQ ID NO. 38) TC02 ETTLTQSPATLSLSPGERATLSCGASQSVSSSYLAWYQQKPGLAPRLL IYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQYNNWP RTFGQGTKVEIK (SEQ ID NO. 40) TD01 QPVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLL IYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDS LNGWFGGGTKLTVL (SEQ ID NO. 41) TE01 DIQMTQSPDSLAVSLGERATINCKSSQSVLDSSNNKNYVAWFQQKPG QPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQ QYYTTRWTFGQGTKVEIK (SEQ ID NO. 42) TG02 DIVMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLI YDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPLT FGGGTKVEIK (SEQ ID NO. 43) TE02.1 QFVLTQSPSASASLGASVKLTCTLSSGHSSYAIAWHHQQPEKGPRYL MKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDEADYYCQT WGTGMLCFGGGTQLTALR (SEQ ID NO. 96) TE02.2 QFVLTQSPSASASLGASVKLTCTLSSGHSSYAIAWHHQQPEKGPRYL MKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDEADYYCQT WGTGMLFGGGTQLTALR (SEQ ID NO. 97) TE02.3 QFVLTQSPSASASLGASVKLTCTLSSGHSSYAIAWHHQQPEKGPRYL MKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDEADYYCQT WGTGMLWFGGGTQLTALR (SEQ ID NO. 98) TE03 QWLTQSPPASASLGASVKLTCTLSSGHSSYAIAWHQQQPEKGPRYL MKLNSDGSHSKGDGIPDRFSGSSSGAERYLTISSLQSEDEADYYCQT WGTGCCFGGGTQLTALR (SEQ ID NO. 99) TE04 QTVVTQESSFSVSPGGTVTLTCGLSSGSVSTSYNPSWYQQTPGQAPR TLIYSTNTRSSGVPDRFSGSILGNKAALTITGAQADDESDYYCVLYMGS GIIFGSGTKVTVL (SEQ ID NO. 100) TE07 QTVVTQEPSFSVSPGGTVTLTCGLSSGSVSTSYYPSWYQQTPGQAPR TLIYSTNTRSSGVPERFSGSILGNKAALTITGAQADDESDYYCVLYMGS GTCCFGGGTQLTALR (SEQ ID NO. 101) TE10 QPVLTQSSSASASLGSSVKLTCTLSSGHSSYIIAWHQQQPGKAPRYLM KLEGSGSYNKGSGVPDRFSGSSSGADRYLTISNLQFEDEADYYCETW DSNTPHAVFGGGTQLTAL (SEQ ID NO. 102) TM1 VIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYLQKPGKAPELLIY PASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFT FGQGTKLEIK (SEQ ID NO. 103) Table 9: VH nucleotide sequences of exemplified antibodies Antibody DNA ofVH TC01 CAAATCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGG GCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACC I I IACCA GCTACGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTG AGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGC ACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCAC GAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACAC GGCCGTGTATTACTGTGCGAGGTGGGGTAGGTGGCTGGCTCATGA CTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO. 45) TC03 CAGATCCAGTTGGTGCAAAGTGGGGCTGAGGTAAAGCAGCCGGGT GCAAGTGTGTCCGTAAGTTGTGCAGCCAGTGGCTACACCI I I ACTA GTTACGGAAI I ICATGGGTGCGGCAAGCTCCCGGTCAGGGATTGG AATGGATGGGATGGAI I I CAGCATACAACGGGAACACAAATTACGC TCAAAAATTGCAGGGTCGAGTTACCATGACTACAGACACGTCTACG TCTACAGCTTACATGGAACI I ICCAGCCTGCGGTCCGACGACACCG CAGI I IATTATTGCGCCCGCTGGGGGAGATGGCTCGCGCATGACT ACTGGGGGCAGGGCACGCTGGTTACCG I I I CCTCAGCCTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCT CCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGT GGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTG CCCAGCACCTGAGTTCGAGGGGGGACCATCAGTCTTCCTGTTCCC CCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGT CACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGT ACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA TC04 AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAA GAGTCTCTCCCTGTCTCTGGGTAAA (SEQ ID NO. 174) CAGATCCAGTTGGTGCAAAGTGGGGCTGAGGTAAAGCAGCCGGGT GCAAGTGTGTCCGTAAGTTGTGCAGCCAGTGGCTACACCTTTACTA GTTACGGAATTTCATGGGTGCGGCAAGCTCCCGGTCAGGGATTGG AATGGATGGGATGGATTTCAGCATACAACGGGAACACAAATTACGC TCAAAAATTGCAGGGTCGAGTTACCATGACTACAGACACGTCTACG TCTACAGCTTACATGGAACTTTCCAGCCTGCGGTCCGACGACACCG CAGTTTATTATTGCGCCCGCTGGGGGAGATGGCTCGCGCATGACT ACTGGGGGCAGGGCACGCTGGTTACCGTTTCCTCAGCCTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCT CCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGT GGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTG CCCAGCACCTGAGTTCGAGGGGGGACCATCAGTCTTCCTGTTCCC CCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGT CACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGT ACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAA GAGTCTCTCCCTGTCTCTGGGTAAA (SEQ ID NO. 175) TC05 CAGATCCAGTTGGTGCAAAGTGGGGCTGAGGTAAAGCAGCCGGGT GCAAGTGTGTCCGTAAGTTGTGCAGCCAGTGGCTACACCI I I ACTA GTTACGGAAI I ICATGGGTGCGGCAAGCTCCCGGTCAGGGATTGG AATGGATGGGATGGAI I I CAGCATACAACGGGAACACAAATTACGC TCAAAAATTGCAGGGTCGAGTTACCATGACTACAGACACGTCTACG TCTACAGCTTACATGGAAC I I I CCAGCCTGCGGTCCGACGACACCG CAGI I IATTATTGCGCCCGCTGGGGGAGATGGCTCGCGCATGACT ACTGGGGGCAGGGCACGCTGGTTACCG I I I CCTCAGCCTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCT CCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGT GGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTG CCCAGCACCTGAGTTCGAGGGGGGACCATCAGTCTTCCTGTTCCC CCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGT CACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGT ACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAA GAGTCTCTCCCTGTCTCTGGGTAAA (SEQ ID NO. 176) TA02 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAGGCCTGG GTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAG CAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCT TGAGTGGATGGGAGGGATCATCCCTATC I I I GGTACAGCAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC ACGAGCACAGCCTACATGGAGCTGAGCAACCTGAGATCTGAGGAC ACGGCCGTGTATTACTGTGCGAGAGGGGATATAGCAGCAGCTGGT AGGAAAGGACTGCCCATCTACTACATGGACGTCTGGGGCAAAGGG ACCACGGTCACCGTCTCCTCA (SEQ ID NO. 44) TC02 CAGATGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGG GTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAG CAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCT TGAGTGGATGGGAGGGATCATCCCTATC I I I GGTACAGCAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCC ACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGAC ACGGCCGTGTATTACTGTGCGAGCCCAAGTGGTTATTATAI I IATG ATGC Illi GATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTC A (SEQ ID NO. 46) TD01 CAGGTCCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGG GCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACC I I IACCA GCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTG AGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGC ACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCAC GAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACAC GGCCGTGTATTACTGTGCGAGAGATCTCGGCTGGCCAGATGACTA CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO. 47) TE01 GAAGTGCAGTTGTTGGAGTCTGGGGGAGGTGTGGTACGGCCTGG GGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACC I I I GAT GATTATGGCATGAGCTGGGTCCGCCAAGCTCCAGGGAAGGGGCTG GAGTGGGTCTCTGGTATTAATTGGAATGGTGGTAGCACAGGTTATG CAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAA GAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACAC GGCTGCGTATTACTGTGCGAAAGATCGACTAAGATATTGTAGTAGT ACCAGCTGCTATATCCCTGACTACTGGGGCCAGGGAACCCTGGTC ACCGTCTCCTCA (SEQ ID NO. 48) TG02 CAGGTGCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGG GGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCI I I ACC AGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTT GAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATG CACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCA CGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACA CGGCCGTGTATTACTGTGCGAGAGTAGGGAGCACTTACGATTTTTG GAGTGGCGCCTACTACTACTACGGTATGGACGTCTGGGGCCAAGG GACCACGGTCACCGTCTCCTCA (SEQ ID NO. 49) TE02.1 CAGGTCCAACTCGTCGAGAGCGGAGGAGGAGTCGTCCAACCCGG AAGGAGCTTGCGGCTATCATGCGCGGCATCCGGCTTCACAI I I I CC CGGCACGGGATGCACTGGGTCAGGCAAGCACCCGGCAAGGGGCT AGAATGGGTCGCGGTCATCTGGTATGATGGAAGGAACAAATACTAT GCCGACTCAGTCAAGGGGCGATTTACAATTTCGCGAGACAACTCCA AGAATACGCTATACCTGCAAATGAACTCGCTGAGGGTCGAGGACAC GGCGGI I IATTACTGCGCGAGGGAGGGGATAACTATGGTCAGAGG AGTCATTCCGCTAI I I GACTATTGGGGGCAGGGTACCTTAGTCACG GTCTCGAGC (SEQ ID NO. 104) TE02.2 CAGGTCCAACTCGTCGAGAGCGGAGGAGGAGTCGTCCAACCCGG AAGGAGCTTGCGGCTATCATGCGCGGCATCCGGCTTCACAI I I I CC CGGCACGGGATGCACTGGGTCAGGCAAGCACCCGGCAAGGGGCT AGAATGGGTCGCGGTCATCTGGTATGATGGAAGGAACAAATACTAT GCCGACTCAGTCAAGGGGCGATTTACAATTTCGCGAGACAACTCCA AGAATACGCTATACCTGCAAATGAACTCGCTGAGGGTCGAGGACAC GGCGG I I IATTACTGCGCGAGGGAGGGGATAACTATGGTCAGAGG AGTCATTCCGCTA I I I GACTATTGGGGGCAGGGTACCTTAGTCACG GTCTCGAGC (SEQ ID NO. 105) TE02.3 CAGGTCCAACTCGTCGAGAGCGGAGGAGGAGTCGTCCAACCCGG AAGGAGCTTGCGGCTATCATGCGCGGCATCCGGCTTCACAI I I I CC CGGCACGGGATGCACTGGGTCAGGCAAGCACCCGGCAAGGGGCT AGAATGGGTCGCGGTCATCTGGTATGATGGAAGGAACAAATACTAT GCCGACTCAGTCAAGGGGCGATTTACAATTTCGCGAGACAACTCCA AGAATACGCTATACCTGCAAATGAACTCGCTGAGGGTCGAGGACAC GGCGG I I IATTACTGCGCGAGGGAGGGGATAACTATGGTCAGAGG AGTCATTCCGCTAI I I GACTATTGGGGGCAGGGTACCTTAGTCACG GTCTCGAGC (SEQ ID NO. 106) TE03 CAGGTCCAACTCGTTGAATCCGGGGGGGGAGTCGTCCAACCGGG GAGAAGCCTGCGGCTAAGCTGCGCGGCTTCGGGATTCACATTCTC TCGATACGGGATGCACTGGGTCAGGCAAGCACCGGGGAAGGGCTT GGAATGGGTCGCCGTCATATGGTACGACGGATCATATAAATATTAT GCTGACTCTATAAAGGGGCGATTCACGGTTAGCCGAGACAACTCCA AAAACACGCTATACCTGCAAATGAACTCACTGCGAGCTGAAGATAC GGCGCTATATTATTGCGCCCGATTCGGAATCCTGACCGGATATTAT I I IGACTACTGGGGGCAGGGTACCCTAGTCACGGTCTCGAGC (SEQ ID NO. 107) TE04 CAGGTCCAACTCGTCGAGAGCGGAGGAGGAGTCGTCCAACCCGG AAGGAGCTTGCGGCTATCATGCGCGGCATCCGGCTTCACAI I I I CC CGGCACGGGATGCACTGGGTCAGGCAAGCACCCGGCAAGGGGCT AGAATGGGTCGCGGTCATCTGGTATGATGGAAGGAACAAATACTAT GCCGACTCAGTCAAGGGGCGATTTACAATTTCGCGAGACAACTCCA AGAATACGCTATACCTGCAAATGAACTCGCTGAGGGTCGAGGACAC GGCGG I I IATTACTGCGCGAGGGAGGGGATAACTATGGTCAGAGG AGTCATTCCGCTA I I I GACTATTGGGGGCAGGGTACCTTAGTCACG GTCTCGAGC (SEQ ID NO. 108) TE07 GAAGTCCAACTGCTGGAATCGGGCGGGGGGCTGGTCCAACCCGG AGGATCATTGAGGCTATCATGCGCCGCTTCCGGCTTTACATTTAGC TCATACGCAATGTCATGGGTCCGACAAGCTCCGGGGGAGGGACTG GAATGGGTCTCTGGGAI I I CGGGCTCTGGATACTCCACATATAGCG CGGACTCAGTCAAGGGGAGATTCACGATTTTTAAGGATAACTCCAA GAATACATTATATCTGCAAATAAACTCGCTGAGGGCGGAGGATACC GCCGI I IATTACTGCGCCAAAGGGAAAGTCGGGCCAACTTACGCAT TCGACCTATGGGGGCAGGGTACCATGGTCACGGTCTCGAGC (SEQ ID NO. 109) TE10 CAAGTGCAACTCGTGGAATCGGGCGGAGGGGTGGTGCAACCGGG AAGATCACTGCGACTATCATGCGCCGCATCGGGATTTACATTTAGC AGCTACGGGATGCACTGGGTCCGCCAAGCACCCGGAAAAGGGCT GGAAIGGGICGCGGIGAI I IGG IACGAI GGC ICGAAI AAAI AC I Al GCTGACTCGGTGAAGGGCCGATTCACAATCTCGCGGGACAACTCC AAAAACACACTATATCTGCAAATGAACTCACTGCGGGCGGAGGATA CCGCGGTATATTACTGCGCGAGGGAGGGGCGCGGAATGGATGTAT GGGGGCAGGGTACCACGGTGACCGTCTCGAGC (SEQ ID NO. 110) TM1 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG GAGGTCCCTGAGACTCTCCTGTGCAGCATCTGGATTCACCTTCAGT ACCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGTTATATGGTATGATGGATATAATAAATACTATGT AGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCGA GAACACGGTGTATCTGCAGATGAACAGCCTGAGAACCGAGGACAC GGCTG I I IATTACTGTGCGAGAGAAGGATGGTTCGGGAAATTATTA TCCGCTCTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTT CA (SEQ ID NO. 111) Table 10: VL nucleotide sequences of exemplified antibodies Antibody DNAofVL TC01 CAGGCAGTGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGA CAGACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGAAATAAAA ATGCTTATTGGTATCAGCAGAAGCCAGGCCAGTCCCCTGTACTGGT CATGTATCAAAGTACCAGACGGCCCTCAGGGATCCCTGAGCGATTC TCTGCCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGG ACCCAGGCTATGGATGAGGCTGACTATTACTGTCAGGCGTGGGAC AGCAGTAGTGGATGGGAGGTATTCGGCGGAGGGACCAAGCTGACC GTCCTA (SEQ ID NO. 51) TC03 CAGGCGGTGCTTACTCAGCCCCCAAGTGTGTCTG I I I CCCCCGGT CAGACTGCGTCTATAACCTGCTCCGGGGATAAACTCGGCAACAAGA ATGCGTACTGGTACCAACAGAAGCCGGGACAGAGCCCAGTCTTGG TCATGTACCAATCCACCCGGAGACCTAGCGGCATTCCAGAGCGCTT TAGTGCATCTAATTCTGGCAATACGGCGACGTTGACCATCAGTGGT ACACAAGCGATGGACGAGGCAGATTACTACTGTCAGGCATGGCTG TCATCATCCGGGTGGGAGGTG I I I GGCGGCGGAACAAAACTCACT GTCCTAGGTCAGCCCAAGGCTGCACCAAGTGTCACTCTGTTCCCG CCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGT CTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAG GCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAG CCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCA GGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTAC AGAATGTTCA (SEQ ID NO. 177) TC04 CAGGCCGTCTTGACTCAACCACCCTCCGTTAGTGTCTCCCCCGGC CAGACGGCGAGTATCACCTGTAGTGGTGATAAGCTGGGCAATAAG AATGCTTACTGGTACCAGCAAAAACCCGGACAGAGCCCAGTGCTG GTGATGTATCAGTCTACAAGACGACCTAGCGGCATCCCAGAAAGGT I I ICTGCCAGCAATTCTGGCAATACGGCGACGCTGACTATTAGTGG CACACAAGCAGAGGATGAGGCGGACTATTACTGCCAAGCATGGGA CAGTAGTAGTGGTTGGGAAGTCTTCGGGGGCGGCACTAAGCTCAC CGTCCTAGGTCAGCCCAAGGCTGCACCAAGTGTCACTCTGTTCCC GCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAA GGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACAC CCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGA GCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCC AGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTA CAGAATGTTCA (SEQ ID NO. 178) TC05 CAAGCTGTATTGACACAACCTCCTAGTGTCAGTGTAAGCCCTGGTC AAACTGCCTCCATTACTTGCTCTGGCGACAAGCTCGGAAATAAGAA CGCGTACTGGTACCAACAGAAGCCCGGACAGTCACCTGTGCTTGT TATGTATCAAAGCACCAGGAGACCTTCAGGGATACCAGAAAGG I I I AGTGCGTCTAATTCCGGGAATACCGCGACACTGACGATAAGCGGC ACTCAGGCTATGGACGAAGCGGATTACTACTGTCAGGCATGGGATT CATCATCAGGTTGGGAAGTATTCGGGGGCGGTACAAAATTGACGG TCCTAGGTCAGCCCAAGGCTGCACCAAGTGTCACTCTGTTCCCGC CCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCT CATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGC AGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTC CAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCT GACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGT CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGA ATGTTCA (SEQ ID NO. 179) TA02 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG GAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCA ACTACTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCT CCTGATCTATGCTGCATCCAG I I I GCAAAGTGGGGTCCCATCAAGG TTCAGTGGCAGTGGATCTGGGACAGAI I I CACTCTCACCATCAGCA GTCTGCAACCTGAAGA Illi GCAACTTACTACTGTCAACAGAGTTAC AGTACCCCTAC Illi GGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO. 50) TC02 GAAACGACACTCACGCAGTCTCCAGCCACCCTGTCI I IGrCTCCAG GGGAAAGAGCCACCCTCTCCTGCGGGGCCAGTCAGAGTGTTAGCA GCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCTGGCGCCCA GGCTCCTCATCTATGATGCATCCAGCAGGGCCACTGGCATCCCAG ACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCAT CAGCAGACTGGAGCCTGAAGAI I I IGCAGI I IATTACTGTCACCAG TATAATAACTGGCCTAGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAA (SEQ ID NO. 52) TD01 CAGCCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGG CAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAA GTAATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAA ACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGAC CGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCA GTGGGCTCCGGTCCGAGGATGAGGCTGATTATTATTGTGCAGCAT GGGATGACAGCCTGAATGGTGTGGTATTCGGCGGAGGGACCAAGC TGACCGTCCTA (SEQ ID NO. 53) TE01 GACATCCAGATGACCCAGTCTCCGGACTCCCTGGCTGTGTCTCTG GGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTG I I I I G GACAGCTCCAACAATAAAAATTATGTCGCTTGGTTCCAGCAGAAAC CAGGACAGCCTCCTAAGCTGCTCAI I IACTGGGCCTCTACCCGGG AATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGTTCTGGGACAG Alli CACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGT TTATTACTGTCAGCAATATTATACTACTCGGTGGACGTTCGGCCAAG GGACCAAGGTGGAAATCAAA (SEQ ID NO. 54) TG02 GACATCGTGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAA ATGAI I IAGGCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAACT CCTGATCTACGATGCATCCAAI I I GGAAACAGGGGTCCCATCAAGG TTCAGTGGAAGTGGATCTGGGACAGAI I I I AC I I ICACCATCAGCA GCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGAT AACCTCCCGCTCAC I I ICGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO. 55) TE02.1 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAAI I IGTGCTGACGCAATCGCCATC GGCTAGTGCATCACTGGGGGCGAGCGTTAAATTGACATGCACGCT ATCGAGCGGACACTCATCATATGCCATTGCATGGCACCACCAACAA CCGGAAAAGGGGCCACGATATCTAATGAAGCTGAACTCTGACGGA TCGCATTCGAAAGGGGATGGGATTCCCGACCGATTCTCGGGAAGC AGCAGCGGAGCTGAAAGATAI I IAACGATATCATCGCTGCAATCGG AGGATGAAGCTGACTACTACTGCCAAACTTGGGGAACGGGGATGC TATGCTTCGGAGGAGGCACACAATTGACGGCCCTTGGACAACCG (SEQ ID NO. 112) TE02.2 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAA I I IGTACTGACGCAAAGCCCAAG CGCGAGCGCATCGCTGGGAGCATCCGTCAAGCTCACATGCACGCT ATCATCGGGCCATTCAAGCTATGCCATAGCATGGCATCACCAACAA CCGGAGAAGGGACCTCGATATCTGATGAAGCTGAATAGCGACGGC TCCCACTCAAAGGGGGACGGAATCCCGGATAGAI I I ICGGGCTCA TCAAGCGGAGCGGAGCGATATCTCACGATCTCTAGCCTGCAAAGC GAGGATGAGGCCGACTACTACTGCCAAACATGGGGGACGGGAATG CTATTCGGAGGAGGCACGCAACTGACGGCGCTGGGGCAACCA (SEQ ID NO. 113) TE02.3 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAA I I IGTGCTGACGCAATCACCATC GGCTTCGGCGAGCCTGGGGGCATCTGTCAAGCTGACATGCACGCT GAGCTCCGGGCATTCATCATATGCCATCGCATGGCATCACCAACAA CCCGAGAAGGGACCACGATATCTCATGAAGCTAAACTCCGACGGA TCGCATTCGAAGGGGGATGGAATACCCGACCGA Illi CGGGATCAT CGAGCGGGGCGGAGAGATAI 1 1 GACGATCTCCTCTCTGCAAAGCG AGGACGAGGCGGACTACTATTGCCAAACCTGGGGCACGGGAATGC TATGG 1 1 1 GGAGGAGGCACACAACTGACGGCGCTGGGCCAACCG (SEQ ID NO. 114) TE03 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAAGTAGTCCTGACTCAAAGCCCCC CGGCGAGCGCATCATTGGGGGCGAGCGTCAAGCTGACATGCACG CTATCGAGCGGGCACTCTAGCTACGCGATAGCATGGCACCAACAA CAACCGGAAAAGGGACCCCGATACTTGATGAAATTAAATAGCGACG GATCGCACTCTAAGGGAGACGGAATACCTGATAGAI I IAGCGGGA GCTCATCGGGGGCGGAGAGATACTTGACGATTAGCTCACTGCAAT CGGAGGATGAGGCGGACTACTATTGCCAAACATGGGGGACGGGAT GCTGCTTCGGAGGAGGCACGCAACTGACCGCATTGGGACAACCA (SEQ ID NO. 115) TE04 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAAACCGTGGTGACACAAGAATCAA Gill IAGCGTATCGCCGGGAGGGACGGTGACGCTGACCTGCGGG CTATCATCTGGATCGGTATCAACATCCTACAATCCGAGCTGGTATC AACAAACGCCCGGACAAGCGCCACGAACCCTGATATATTCGACAAA TACCCGATCATCTGGGGTGCCGGATAGA Illi CCGGCTCGATTCTG GGAAACAAGGCTGCGCTGACGATAACCGGAGCTCAAGCCGACGAT GAGAGCGATTATTATTGCGTGCTATACATGGGGAGCGGGATTATAT TCGGATCTGGAACGAAAGTCACGGTGCTAGGACAACCG (SEQ ID NO. 116) TE07 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAAACGGTCGTCACGCAAGAGCCAT CCTTCTCGGTCTCGCCGGGGGGGACGGTCACACTGACATGCGGG CTGAGCTCGGGATCGGTCTCAACGAGCTACTACCCGAGCTGGTAT CAACAAACACCGGGGCAAGCACCGCGGACGCTGATATATTCCACA AATACACGGAGCTCCGGTGTCCCGGAGAGATTCTCGGGATCAATA CTGGGGAACAAGGCGGCTCTGACGATAACCGGAGCCCAAGCGGAT GACGAATCGGACTATTACTGCGTCCTATACATGGGCTCCGGCACAT GCTGC I I I GGAGGAGGCACACAACTGACGGCGCTGGGACAACCT (SEQ ID NO. 117) TE10 GCGGCCGCCATGAAI I I I GGACTGAGGCTGAI I I ICCTGGTGCTGA CCCTGAAAGGCGTCCAGTGTCAGCCGG Illi GACGCAATCTAGCA GCGCATCCGCTAGTCTTGGAAGCTCCGTGAAGCTGACATGCACAC TATCATCGGGGCATTCCTCCTACATAATTGCATGGCATCAACAACAA CCCGGCAAGGCCCCGAGATACTTAATGAAACTGGAAGGATCGGGA TCATATAACAAAGGATCGGGGGTGCCGGATAGAI I IAGCGGATCTA GCTCTGGGGCTGACCGATACCTGACGATCTCTAATCTGCAAI I I GA GGACGAGGCCGATTACTACTGCGAAACATGGGATAGCAACACCCC ACACGCGGTAI I I GGAGGAGGCACCCAATTGACCGCGCTAGGCCA ACCA (SEQ ID NO. 118) TM1 GTCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG GAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAA ATGAI I IAGGCTGGTATCTGCAGAAACCAGGGAAAGCCCCTGAGCT CCTGATCTATCCTGCATCCAG I I IACAAAGTGGGGTCCCGTCAAGG TTCAGCGGCAGTGGATCTGGCACAGAI I I CACTCTCACCATCAGCA GCCTGCAGCCTGAAGA Illi GCAACTTATTACTGTCTACAAGATTAC AATTACCCGTTCAC Illi GGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO. 119) Table 11: Constant region amino acid sequences Constant region AA Human lgG4 heavy chain P01861.1 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFP PKPKDTLMISRTP E VTC VWD VS Q E D P E VQ F N WYVD G VE VH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNK GLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSR LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO. 120) Human lgG4 heavy ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW chain NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFP PKPKDTLMISRTP E VTC VWD VS Q E D P E VQ F N WYVD G VE VH NAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNK GLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSR LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO. 180) Human lgG2 heavy ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW chain P01859 NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSNFGTQTYT CNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFP PKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWYVDGVEVH N AKTKP R E E Q F N STF RWS VLTWH Q D WLN G KE YKC KVS N KGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO. 121) Human lgG1 heavy ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW chain, gamma 1 NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYIC P01857 NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMIS RTP E VTC VWD VS H E D P E VKF N WYVD G V EVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP ELQLEESCAEAQDGELDGLWTTITIFITLFLLSVCYSATVTFFK VKWIFSSVVDLKQTIIPDYRNMIGQGA (SEQ ID NO. 181) Human light chain, GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW lambda 1 KADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSH P0CG04 RSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO. 122) Human light chain, GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW lambda 2 KADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHR P0DOY2 SYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO. 123) Human light chain, kappa P01834 RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO. 124) EXAMPLES Material and methods In vivo experimental design As shown in Figure 1, after a single intraperitoneal injection of AOM (10 mg / kg body weight in physiological solution), mice were treated with repeated oral cycles of the inflammatory agent, 2% (weight / volume) DSS (molecular mass 40 kDa) (MP Biomedicals), each characterized by 7 days of DSS exposure in drinking water, followed by 7 days of regular drinking water, according to the scheme of Figure 1 (12). The 40 kDa DSS-induced Inflammation model, as the one used in this study, affords a high degree of uniformity and reproducibility of most lesions in the distal colon, where an enormous number of microorganisms live, whereas less inflammation is observed in the proximal site and almost none in the caecum. On the contrary, mice treated with 5 kDa DSS develop relatively patchy lesions mainly in the cecum and upper colon (18-20). The design of the study is summarized in Figure 2. EntOOI is the antibody described herein and in WO2021094620 as TC01. The study included a set of control groups, as outlined below, aimed at testing: 1) the effect of intraperitoneal administrations of vehicle (i.e. PBS) in the absence of any other agent (Group 1); 2) the effect of intraperitoneal administrations of EntOOI alone in the absence of any other agent (Group 2); 3) the effect of intraperitoneal administrations of EntOOI in combination with the carcinogenic agent AOM without DSS (Group 3); 4) the effect of intraperitoneal administrations of EntOOI in combination with the pro-inflammatory agent DSS without AOM (Group 4) and the effect of intraperitoneal administrations of anti-murine TNFa antibody, used as positive control (Group 6). The other experimental groups in the study aimed at testing the effect of intraperitoneal administrations of EntOOI alone (Group 5) or in combination with the anti-murine TNFa antibody (Group 7). 1) Vehicle (N=8 mice) 2) EntOOI alone (no AOM / no DSS) (N=8 mice) 3) AOM + EntOOI (N=8 mice) 4) DSS + EntOOI + Vehicle (N=8 mice) 5) AOM / DSS + EntOOI (N=8 mice) 6) AOM / DSS + anti-murine TNFalpha antibody (N=8 mice) 7) AOM / DSS + anti-murine TNFalpha antibody + EntOOI (N=8 mice) Of note, the commercial anti-murine TNFalpha antibody clone MP6-XT22 (eBioscience, San Diego, CA) was used, since it displayed beneficial effects, at the indicated dose, in the DSS-induced model of colitis, as documented by the literature (13). Clinical and Physical Examination: Disease Activity Index & Body Weight Loss Colitis seventy was monitored using a disease activity index (DAI) score based on daily evaluation of body weight, stool consistency, and presence of blood in the stools; grading of intestinal inflammation was determined according to the criteria proposed by Cooper et al. (14, 15); the DAI was determined by scoring changes in: weight loss (0 = none, 1 = 1 %—5%, 2 = 5%-10%, 3 = 10%-20%, 4 = >20%); stool consistency (0 = normal, 2 = loose, 4 = diarrhoea); and rectal bleeding (0 = normal, 2 = occult bleeding, 4 = gross bleeding). A 5-point (0-4) DAI was thus obtained as the mean of the three parameter scores. Tissue sampling At Day 56, mice were euthanized by CO2, colons excised (without caecum), and collected to perform the following analyses: - Measurement of colon length, as an additional parameter of intestinal inflammation. - Histological analysis: whole colons were fixed in formalin and embedded in paraffin, in order to perform histologic inflammatory scores and evaluation of tumor density, grade and size. - Quantification of intestinal epithelial cell proliferation: mice (n=4 per group) were administered with 5-Bromo-2'-deoxyuridine (Brdll, from Merck Life Science S.r.l.) by intraperitoneal injection, 1 hour before sacrifice. Formalin-fixed and paraffin-embedded sections were stained using an anti-Brdll antibody and Brdll-positive nuclei were quantified using an imaging system. - Quantification of cleaved Caspase 8: as an additional readout to confirm the efficient inhibition of IGFBP3, we quantified IGFBP3-dependent apoptotic molecule cleaved Caspase 8 in the intestinal mucosa of n=4 animals per group, by western blot. Assessment of histological colonic lesions Grading of intestinal inflammation was confirmed histologically. At sacrifice, colons were fixed in 10% formalin for 24-48 hour at room temperature. Tissues were then dehydrated through 70%, 80%, and 95% alcohol, 45 min each, followed by 3 changes of 100% alcohol, 1 hour each. Colons were then cleared through 2 changes of xylene, 1 hour each, and then immersed in 3 changes of paraffin, 1 hour each. 2-pM paraffin-embedded sections were obtained using a microtome and transferred onto glass slides suitable for immunohistochemistry (Superfrost Plus). Upon staining with hematoxylin (Dako) and eosin (Diapath), a blinded pathologist evaluated the degree of inflammatory cell infiltration and mucosal damage on colon sections, using 2 different protocols: 1) Rachimilewitz score (16). This scoring system takes into account the ulceration, extent of ulceration, flogosis, extent of flogosis and fibrosis in the whole colon section, without distinguishing into proximal and distal colon. Minimal score was 0, and maximal score was 20, as a sum of all single scores (Total histologic score). 2) Histologic score, as described by Dieleman et al. (17). The sections were graded in the proximal and distal colons (Figure 3) by a blinded pathologist with a range from 0 to 3 as to amount of inflammation, depth of inflammation and with a range from 0 to 4 as to the amount of crypt damage or regeneration as indicated in Table 12. These changes were also quantified as to the percentage involvement by the disease process: (1) 1-25%; (2) 26-50%; (3) 51-75%; (4) 76-100%. Each section was then scored for each feature separately by establishing the product of the grade for that feature and the percentage involvement (in a range from 0 to 12 for inflammation and for extent, and in a range from 0 to 16 for regeneration and for crypt damage). Total histological score was calculated as the sum of the score products (in a range from 0 to 56). Table 12. Histologic score by Dieleman et al. Dieleman et al. Inflammation 0 None 1 Slight 2 Moderate 3 Severe Extent 0 None 1 Mucosa 2 Mucosa and submucosa 3 Transmural Regeneration 0 Complete regeneration or normal tissue 1 Almost complete regeneration 2 Regeneration with crypt depletion 3 Surface epithelium not intact 4 No tissue repair Crypt damage 0 None 1 Basal 1 / 3 damaged 2 Basal 2 / 3 damaged 3 Only surface epithelium intact 4 Entire crypt and epithelium lost Percent involvement 1 1-25% 2 26-50% 3 51-75% 4 76-100% Analysis and grading of tumor lesions Typically, colons of animals that have been treated with AOM / DSS are found to have 5 occasional, abnormally large, darkly staining, and slightly raised ‘aberrant crypts’, called glandular intraepithelial neoplasia (GIN), after 3-4 weeks from the AOM injection (around Day 14 to Day 21 of the present study). With longer time intervals between carcinogen administration and inflammation, these aberrant crypts are frequently found as foci, with two to many hundreds of aberrant crypts appearing together in a cluster, after 5-7 weeks 10 (around Day 28 to Day 42 of the present study) from AOM injection. Typically, many aberrant crypts on histological examination show a low and a high level of dysplasia and are then correctly called adenoma, which may evolve to non-metastatic colon carcinomas at 7-8 weeks (around Day 42 to Day 56 of the present study) (Figure 4). Thus, in the current experiment, four grades of mucosal lesions were identified and quantified by a blinded pathologist: glandular intraepithelial neoplasia (GIN), indicating small clusters of dysplastic colonic crypts on the mucosal surface, low grade (LG) and high-grade (HG) adenomas, and in situ carcinoma (K) (12, 21). Mice were sacrificed at Day 56, seven days after the fourth DSS cycle, and during the recovery phase in water. This was done because around this time point not only are there higher chances to find different grades of tumoral lesions, including in situ carcinoma, but also because the reduced inflammation during recovery allows a better visualization and quantification of neoplastic lesions. BrdU quantification on colon sections To achieve labelling of epithelial cells undergoing DNA synthesis, mice (n=4 per group) received an i.p. injection of 100 mg / kg Brdll 1 hour prior to sacrifice. Formalin-fixed, paraffin-embedded colon sections (2-pm) were stained for Brdll after antigen retrieval for 30 minutes at 98°C in citric buffer (10 mM, pH 6.0). Following endogenous peroxidase blocking with peroxidase 1 solution for 20 minutes at RT, tissues were washed in TBS. Upon incubation with the rat anti-BrdU Ab (1:600; AbD Serotec) for 40 minutes at 4°C, a rat HRP polymer kit (Biocare Medical) was used to detect BrdU using DAB (Biocare Medical) as chromogen. Tissue sections were then counterstained with CAT Hematoxylin (Biocare Medical), dried overnight in a 37°C oven, and mounted in Eukitt Quick Hardening Mounting Media. Images were acquired with a VS120 Dot Slide System (Olympus), and BrdU+ cells were counted in consecutive and randomly selected 10x fields (n = 4 fields of 1 mm2 / section) using the IHC Tool Box of Imaged 1.80p (see examples below). We distinguished inflammatory from tumor areas. Non-inflammatory (control groups) and inflammatory areas (colitic and tumor-bearing mice): upon definition of the region of interest (ROI) (1 mm2), containing all mucosa layers (whenever possible), BrdU-positive nuclei with different sizes were selected using the ellipse tool, through the TRAINING-NUCLEI function. Image J automatically processes the image and calculates the number of nuclei within the selected region. Tumor areas: in this case, nuclei segmentation and quantification was performed in selected tumor areas calculated in pixels on a 20x magnification, and results are reported as number of BrdU-positive nuclei per tumor area. Quantification of cleaved Caspase 8 by western blot Colonic samples (1 entire colon from 1 mouse per group + 1 small specimen from the proximal colon of 3 mice per group) were mechanically homogenized in lysis buffer (Tris 50 mM, 2% SDS, 1 mM Na2VO2) containing proteinase inhibitors (Complete Mini, Roche Diagnostics GmbH, Penzberg, Germany), for protein extraction. Insoluble material was removed by centrifugation for 30 min at 14,000 rpm at 4°C. The concentration of proteins in each lysate was measured using the Bio-Rad protein assay (Bio-Rad Laboratories). Next, proteins from each sample were separated on a 10% Tris-glycine polyacrylamide gel at 160 V for 80 minutes and blotted onto PVDF-membranes (Millipore, Schwalbach, Germany) at 80 mA for 90 min. Membrane was cut according to protein weight and nonspecific binding was blocked with Tris-buffered saline (TBS) containing 5% non-fat dried milk and 0.1% Tween 20, followed by overnight incubation at 4°C with the rabbit anti-mouse Caspase 8 antibody which recognizes the active / cleaved form of Caspase 8 antibody (NB100-56116 from Novus Biological); 1:2000), and with a rabbit anti Caspase-8 antibody (Cell Signaling Technology, #4927; 1:500). Membranes were washed for 1 h with TBS containing 0.1% Tween 20 and then incubated for 1 h with the appropriate horseradish peroxidase-conjugated secondary antibody (1:3000; GE Healthcare). The membranes were then incubated with Immobilon Western Chemilum (Millipore) for 1-5 minutes, after which bands were detected by Chemidoc (BioRad Laboratories), using Quantity One software. The filter was then stripped with buffer Restore (Pierce) and reprobed with a mouse anti-actin antibody (clone C11; 1:1000; Santa Cruz Biotechnology) for control protein loading. Protein bands were quantified using the densitometry program Image J. Statistical analysis Statistical analyses were performed using GraphPad Prism 7 (GraphPad Software). Data are presented as mean ± Standard Error of Mean (SEM) and differences were considered statistically significant when P < 0.05. For experiments including more groups a one-way or two-way ANOVA multivariate analysis has been performed accompanied by a post-hoc modification test. RESULTS Example 1 Clinical and Physical Examinations: Disease Activity Index & Body Weight Loss After 2 weeks of treatments (Day 18-33, treatment every day), results show that EntOOI significantly inhibits experimental colitis in comparison with control group (AOM / DSS + vehicle), in terms of percentage of body weight loss (Figure 5A) and DAI (Figure 5B). Statistical analyses and p values of specific groups at each time point can be found in following Tables 13 and 14. Table 13 Groups Timepoints 0 3 5 7 10 12 14 16 18 21 24 26 28 31 33 35 38 40 42 45 47 49 51 53 56 Vehicle vs. EntOOI ns ns ns ns * ** ** ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns Vehicle vs. AOM / DSS + Vehicle ns **** *♦** **** **** ***♦ »**♦ **** *»»* **** *»** *♦** **** **** ♦ *** »*** AOM / DSS + Vehicle vs. AOM / DSS + EntOOI ns * ns * ** ns ns **** **** **** **** **** AOM / DSS + Vehicle vs. AOM / DSS + anti-FNF ns ns ns * »*** * * ns **** ns **** ***« ***♦ **** AOM / DSS + Vehicle vs. AOM / DSS + anti-FNF+EntOOl ns ns ns ns ns ns ns *♦ ** **** **»* *♦** ♦♦♦ ♦ **** *♦** **** AOM / DSS + EntOOI short vs. AOM / DSS + EntOOI ns ns ns ns ns ns ns * ns ns ns ns ** ** * **** ns ** # * **** ♦ *** AOM / DSS + EntOOI short vs. AOM / DSS + anti-TNF ns ns ns ns ns ns ns ns ns *»*♦ *»** **** **** **** *♦** ns ns **** ns **** *»*♦ **** **** AOM / DSS + EntOOI long vs. AOM / DSS + anti-TNF ns ns ns ns ns ns ns ns ns **** AOM / DSS + EntOOI long vs. AOM / DSS + anti-TNF+EntOOl ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns *** * ns * ns ns ns ns ns ns Table 14 Groups Timepoints 0 3 5 7 10 12 14 16 18 21 24 26 28 31 33 35 38 40 42 45 47 49 51 53 56 Vehicle vs. EntOOI ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns Vehicle vs. AOM / DSS + Vehicle ns **** **** **** **** **** **** **** **** **** **** **** **** **** **** **** **** **** AOM / DSS + Vehicle vs. AOM / DSS + EntOOI ns ns ns ns ns ns ns ns ns **** *»** **** **** **** ♦ ♦♦* *♦** ***♦ **** AOM / DSS + Vehicle vs. AOM / DSS + anti-TNF ns ns ns ns ns ns ns ns ns t*** **** **** ***♦ ♦ *** **** *♦** **** **** AOM / DSS + Vehicle vs. AOM / DSS + anti-FNF+EntOOl ns ns ns ns ns ns ns ns ns **** »«** ♦ ♦♦* **** **** ««*« **♦* *$** **** «**» AOM / DSS + EntOOI short vs. AOM / DSS + EntOOl ns ns ns ns ns ns ns ns ns ns ns ** ns ns ns **** **** **** AOM / DSS + EntOOI short vs. AOM / DSS + anti-FNF ns ns ns ns ns ns ns ns ns *** «**» »* ns **** **** **$* *** * * ns AOM / DSS + EntOOI long vs. AOM / DSS + anti- FNF ns ns ns ns ns ns ns ns ns **** **** **** **** **** **** **** **** **** **** **** **** AOM / DSS + EntOOI long vs. AOM / DSS + anti-FNF+EntOOl ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns * ns Of note, EntOOI was significantly more effective than anti-murine TNFalpha in reducing body weight loss and DAI, at all-time points between Day 18 and Day 33. Combination of anti-murine TNFalpha + EntOOI was no more effective than EntOOI alone. In the following weeks (treatment 2 times per week), results confirmed the statistically significant inhibitory effect of EntOOI on experimental colitis also from Day 33 to Day 56, in comparison with control group (AOM / DSS + vehicle), in terms of body weight loss (Figure 5A) and DAI (Figure 5B). Again, EntOOI was significantly more effective than anti-murine TNFalpha in reducing both these clinical parameters of inflammation, whereas combination of anti-murine TNFalpha + EntOOI was no more effective than EntOOI alone. As shown in Figure 6, at sacrifice (Day 56), all treatment groups showed a significantly lower DAI than AOM / DSS + vehicle group. Of note, treatment with EntOOI resulted in a much better control on DAI compared to anti-murine TNFalpha (anti-TNF). Example 2 Post-mortem analysis of colon length Colon shortening is a parameter of intestinal inflammation (20). At Day 56 mice were sacrificed, and colon lengths were measured. Results confirmed the statistically significant inhibitory effect of EntOOI on the severity of colitis in comparison with control group (AOM / DSS + vehicle) (Figure 7). EntOOI, when administered from Day 18 to Day 55, was significantly more effective than antimurine TNFalpha in reducing colon shortening, and combination of anti-murine TNFalpha + EntOOI was as effective as EntOOI alone. Example 3 Evaluation of colonic inflammation at the histological level The protective effects of EntOOI in DSS-induced chronic colitis were confirmed by a blinded pathologist using the histologic score by Rachmilewitz et al (16) and Dieleman etal (17). According to the Rachmilewitz score, performed on the whole colon, results show that EntOOI significantly improved colitis (Figure 8) compared to control group (AOM / DSS + vehicle) in terms of total histological score. According to the Dieleman score, performed separately on the proximal and distal colon, results show that EntOOI significantly inhibited experimental colitis in comparison with control group (AOM / DSS + vehicle), in terms of total histologic score (Figure 9A), severity of inflammation (Figure 9B), extent of inflammation (Figure 9C), regeneration (Figure 9D) and crypt damage (Figure 9E). In both proximal and distal colons there were no statistically significant differences between groups treated with EntOOI and antimurine TNFalpha. Representative images of inflammatory conditions per group are shown in Figure 10. In healthy mice (e.g. Vehicle), the tissue layers (mucosa, muscularis mucosae, submucosa and muscularis propria) are well structured. Administrations of AOM + EntOOI, or EntOOI alone do not affect the layer composition and there is no inflammatory infiltrate. In DSS-induced colitic mice (e.g. AOM / DSS + vehicle), layer stratification is not maintained anymore, a massive inflammatory infiltrate completely occupies both mucosa and submucosa, and crypts are severely damaged in most part of the colon. The epithelium is eroded indicating the presence of ulcerations. Treatment with EntOOI significantly ameliorated experimental colitis: tissue layers are maintained, there is a slight inflammation with inflammatory cells infiltrating both mucosa and submucosa, but both epithelium and crypts are well structured. At the histological level we observed no major differences between groups treated with EntOOI or antimurine TNFalpha or the combination of EntOOI and anti-murine TNFalpha. Example 4 Analysis & grading of tumor lesions The objective of this study was to identify a potential effect of modulation, in terms of tumor initiation and promotion, tumor growth, or tumor protection in the AOM / DSS mouse model of colitis-associated cancer. When we looked at the total tumor density, i.e. total number of tumors / mouse, we found no tumors in the vehicle (as expected), EntOOI, AOM + EntOOI and DSS + EntOOI groups, indicating that EntOOI antibody does neither induces nor accelerates tumor initiation in the colon (Figure 11). In AOM / DSS treated mice, we observed a certain number of tumors per mouse, that were significantly reduced by treatment with EntOOI and / or anti-murine TNFalpha. In terms of tumor grade, we observed no significative differences in GIN density among the various groups (Figure 12). This is not surprising, since GIN are neoplastic lesions that develop around 3-4 weeks after AOM injection, when we just started to treat mice with EntOOI and / or anti-murine TNFalpha. On the contrary we observed a significant reduction in the density of LGA and HGA in tumorbearing mice treated with EntOOI and / or anti-murine TNFalpha in comparison with AOM / DSS + vehicle control group (Figure 12).Of note, progression from adenoma (LGA / HGA) to carcinoma (K) was observed only for the AOM / DSS + vehicle , with a significantly higher number in the control group (Figure 12), suggesting that EntOOI blocks AOM / DSS-induced tumor progression. When we looked at the tumor size, we found significant reduction in the AOM / DSS + EntOOI group when compared to AOM / DSS + vehicle, both for LGA and HGA (Figure 13), and a trend for the other groups. . These results could be due to a direct effect of EntOOI antibody on intestinal epithelial biologic functions (e.g. proliferation), whereas anti-murine TNFalpha acts only indirectly on tumor growth by modulating inflammation. Representative images of tumor size variation in LGA, HGA and K tumors are shown in Figure 14. Example 5 BrdU quantification on colon sections In order to evaluate the impact of EntOOI on intestinal epithelial cell proliferation, mice (n=4 per group) received an i.p. injection of 100 mg / kg Brdll 1 hour prior to sacrifice, time that allows incorporation of Brdll solely by proliferating intestinal epithelium and not by other cell types with slower cell cycle (e.g. leukocytes). Formalin-fixed, paraffin-embedded, colon sections were stained using an anti-BrdU antibody. BrdU-positive nuclei were quantified in non-inflammatory (control groups), inflammatory (colitic and tumor-bearing mice) and tumor areas, as described above. In inflammatory areas of AOM / DSS mice, the number of BrdU-positive nuclei was significantly increased compared to Vehicle group, due to accelerated epithelial cell turnover caused by chronic inflammation in combination with DNA damage caused by AOM (22). In both non-inflammatory and inflammatory regions, results showed that treatment with EntOOI alone in the presence or absence of AOM, or in DSS-induced colitic mice, did not affect epithelial cell proliferation (Figure 15 and 16). In AOM / DSS mice, treatment with EntOOI and anti-murine TNFalpha significantly reduced the number of BrdU-positive nuclei / mm2when compared with AOM / DSS + vehicle. Within tumors (i.e. LGA), treatment with EntOOI significantly reduced the number of BrdU-positive nuclei per tumor area, while AOM / DSS + anti-murine TNFalpha did not (Figure 17 and 18). This data indicates that EntOOI might impact intestinal epithelial cell proliferation. Example 6 Quantification of cleaved Caspase 8 In order to confirm the efficient inhibition of IGFBP3-dependent Caspase 8 activation by EntOOI, we quantified cleaved Caspase 8 and total Caspase 8 protein in the colon lysates from n=4 animals per group (1 whole colon + 3 small proximal pieces from 3 65 mice), by western blot. Lysates from the same group were pooled to increase the total amount of proteins. Upon normalization with the loading control (actin), results showed that the ratio of Cleaved Caspase 8 / total Caspase 8 is reduced in mice treated with EntOOI (Figure 19), confirming efficacy for EntOOI. Conclusions This study showed that in the AOM / DSS model of colon carcinogenesis, EntOOI not only does not induce or accelerate tumor initiation in the colon, but also significantly reduces tumor density, size and progression. A potential synergist or antagonistic effect of EntOOI with anti-murine TNFalpha on tumor modulation was also evaluated and results indicated that the combination of anti-murine TNFalpha + EntOOI is as effective as EntOOI alone, and therefore no more effective than treatment with EntOOI alone. These data support TMEM219 as a potential therapeutic target for the treatment of colon cancer, in particular of colitis-associated cancer, and for reducing incidence of new colon cancer in IBD patients. REFERENCES 1. Sung, H., et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209-249. https: / / doi.org / 10.3322 / caac.21660 2. Sawicki, T., et al., A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers. 2021; 13, 2025. https: / / doi.Org / 10.3390 / cancers13092025 3. Brenner, H., Kloor, M., and Pox, C. P., Colorectal cancer. The Lancet. 2014; 383(9927): 1490-1502. https: / / doi.Org / 10.1016 / S0140-6736(13)61649-9 4. Siegel, R.L., et al., Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023; 73(3): 233-254. doi:10.3322 / caac.21772 5. Dan, W., et al., Update and latest advances in mechanisms and management of colitis-associated colorectal cancer. World J Gastrointest Oncol. 2023 August 15; 15(8): 1317-1331. doi: 10.4251 / wjgo.v15.i8.1317 6. Schmitt, M., and Greten, F., R., The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol. 2021 Oct;21 (10):653-667. doi: 10.1038 / s41577-021-00534-x 7. PDQ® Adult Treatment Editorial Board. PDQ Colon Cancer Treatment. Bethesda, MD: National Cancer Institute. Available at: https: / / www.cancer.gov / types / colorectal / hp / colon-treatment-pdq. Accessed <01 / 23 / 2024>. [PMID: 26389297] 8. Xie, YH., Chen, YX. & Fang, JY. Comprehensive review of targeted therapy for colorectal cancer. Sig Transduct Target Ther 5, 22 (2020). doi: 10.1038 / s41392-020-0116-z 9. Van K. Morris et al., Treatment of Metastatic Colorectal Cancer: ASCO Guideline. JCO 41,678-700(2023). doi:10.1200 / JC0.22.01690 10. Lu, J., et al., Thalidomide Attenuates Colitis and Is Associated with the Suppression of M1 Macrophage Polarization by Targeting the Transcription Factor IRF5. Dig Dis Sci 2021; 66: 3803-3812. doi: 10.1007 / s10620-021-07067-2 11. Zhou, R.W., Harpaz, N., Itzkowitz, S.H. et al. Molecular mechanisms in colitis-associated colorectal cancer. Oncogenesis 12,    48    (2023). https: / / doi.orq / 10.1038 / s41389-023-00492-0 12. Fazio V, Robertis M, Massi E, et al. The AOM / DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J Carcinog 2011; 10: 9. DOI: 10.4103 / 1477-3163.78279 13.Xiao Y-T, Yan W-H, Cao Y, et al. Neutralization of IL-6 and TNF-a ameliorates intestinal permeability in DSS-induced colitis. Cytokine 2016; 83: 189-192. 14. Cooper HS, Murthy SN, Shah RS, et al. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993; 69: 238-49. PMID: 8350599 15. D’Alessio S, Correale C, Tacconi C, et al. VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest 2014; 124: 3863-3878. DOI: 10.1172 / JCI72189 16. Rachmilewitz D, Karmeli F, Takabayashi K, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 2002; 122: 1428-1441. 17.Dieleman, Palmen, Akol, et al. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol 1998; 114: 385-391. DOI: 10.1046 / j. 1365-2249.1998.00728.x 18. Perse M, Cerar A. Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks. J Biomed Biotechnol 2012; 2012: 1-13. DOI: 10.1155 / 2012 / 718617 19. KITAJIMA S, TAKUMA S, MORIMOTO M. Histological Analysis of Murine Colitis Induced by Dextran Sulfate Sodium of Different Molecular Weights. Exp Anim 2000; 49: 9-15. 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Claims

1. An antibody that binds to TMEM219 receptor or an antigen binding fragment thereof for use in the prevention and / or treatment of colorectal cancer, and / or reducing risk of developing colorectal cancer, such as colitis-associated colorectal cancer (CAC), in patients with inflammatory bowel disease (IBD), wherein said antibody inhibits or reduces the binding of IGFBP3 to said TMEM219 receptor and / or inhibits, reduces, or neutralizes the activation of the TMEM219 receptor induced by binding of IGFBP3 and / or does not activate TMEM219 pathway upon binding to TMEM219 receptor.

2. The antibody for the use according to claim 1 wherein said colorectal cancer is selected from the group consisting of colon cancer, bowel cancer, and rectal cancer.

3. The antibody for the use according to any one of claims 1 -2 wherein said cancer is colitis-associated colorectal cancer.

4. The antibody for the use according to any one of claims 1 -3 wherein said antibody comprises:a. a heavy chain variable domain (VH) comprising:i. a CDR1 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 8, 1, 10, 56, 59, 62, 65 and 68;ii. a CDR2 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 5, 2, 11, 57, 60, 63, 66 and 69; andiii. a CDR3 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 6, 3, 7, 9, 12, 13, 58, 61,64, 67 and 70; and / orb. a light chain variable domain (VL) comprising:i. a CDR1 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 17, 14, 20, 23, 26, 29, 71, 77, 80, 82 and 85;ii. a CDR2 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 18, 15, 21,24, 27, 30, 72, 78, 83 and 86; andiii. a CDR3 sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, 16, 22, 25, 28, 31, 73, 74, 75, 76, 79, 81, 84, 87 and 166.

5. The antibody for the use according to any one of claims 1 -4 wherein said antibody comprises (a) a heavy chain variable region (VH) comprising a VHCDR1, a VHCDR2, a VHCDR3, and (b) a light chain variable region (VL) comprising a VLCDR1, a VLCDR2, and a VLCDR3, wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 8, VHCDR2 consists of the sequence of SEQ ID NO: 5, VHCDR3 consists of the sequence of SEQ ID NO: 6, VLCDR1 consists of the sequence of SEQ ID NO: 17, VLCDR2 consists of the sequence of SEQ ID NO: 18 and VLCDR3 consists of the sequence of SEQ ID NO: 19; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 8, VHCDR2 consists of the sequence of SEQ ID NO: 5, VHCDR3 consists of the sequence of SEQ ID NO: 6, VLCDR1 consists of the sequence of SEQ ID NO: 17, VLCDR2 consists of the sequence of SEQ ID NO: 18 and VLCDR3 consists of the sequence of SEQ ID NO: 166; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 1, VHCDR2 consists of the sequence of SEQ ID NO: 2, VHCDR3 consists of the sequence of SEQ ID NO: 3, VLCDR1 consists of the sequence of SEQ ID NO: 14, VLCDR2 consists of the sequence of SEQ ID NO: 15, and VLCDR3 consists of the sequence of SEQ ID NO: 16; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 1, VHCDR2 consists of the sequence of SEQ ID NO: 2, VHCDR3 consists of the sequence of SEQ ID NO: 7, VLCDR1 consists of the sequence of SEQ ID NO: 20, VLCDR2 consists of the sequence of SEQ ID NO: 21, and VLCDR3 consists of the sequence of SEQ ID NO: 22; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 8, VHCDR2 consists of the sequence of SEQ ID NO: 5, VHCDR3 consists of the sequence of SEQ ID NO: 9, VLCDR1 consists of the sequence of SEQ ID NO: 23, VLCDR2 consists of the sequence of SEQ ID NO: 24, and VLCDR3 consists of the sequence of SEQ ID NO: 25; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 10, VHCDR2 consists of the sequence of SEQ ID NO: 11, VHCDR3 consists of the sequence of SEQ ID NO: 12, VLCDR1 consists of the sequence of SEQ ID NO: 26, VLCDR2 consists ofthe sequence of SEQ ID NO: 27, and VLCDR3 consists of the sequence of SEQ ID NO: 28; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 8, VHCDR2 consists of the sequence of SEQ ID NO: 5, VHCDR3 consists of the sequence of SEQ ID NO: 13, VLCDR1 consists of the sequence of SEQ ID NO: 29, VLCDR2 consists of the sequence of SEQ ID NO: 30, and VLCDR3 consists of the sequence of SEQ ID NO: 31; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 56, VHCDR2 consists of the sequence of SEQ ID NO: 57, VHCDR3 consists of the sequence of SEQ ID NO: 58, VLCDR1 consists of the sequence of SEQ ID NO: 71, VLCDR2 consists of the sequence of SEQ ID NO: 72, and VLCDR3 consists of the sequence of SEQ ID NO: 73; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 56, VHCDR2 consists of the sequence of SEQ ID NO: 57, VHCDR3 consists of the sequence of SEQ ID NO: 58, VLCDR1 consists of the sequence of SEQ ID NO: 71, VLCDR2 consists of the sequence of SEQ ID NO: 72, and VLCDR3 consists of the sequence of SEQ ID NO: 74; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 56, VHCDR2 consists of the sequence of SEQ ID NO: 57, VHCDR3 consists of the sequence of SEQ ID NO: 58, VLCDR1 consists of the sequence of SEQ ID NO: 71, VLCDR2 consists of the sequence of SEQ ID NO: 72, and VLCDR3 consists of the sequence of SEQ ID NO: 75; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 59, VHCDR2 consists of the sequence of SEQ ID NO: 60, VHCDR3 consists of the sequence of SEQ ID NO: 61, VLCDR1 consists of the sequence of SEQ ID NO: 71, VLCDR2 consists of the sequence of SEQ ID NO: 72, and VLCDR3 consists of the sequence of SEQ ID NO: 76; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 56, VHCDR2 consists of the sequence of SEQ ID NO: 57, VHCDR3 consists of the sequence of SEQ ID NO: 58, VLCDR1 consists of the sequence of SEQ ID NO: 77, VLCDR2 consists of the sequence of SEQ ID NO: 78, and VLCDR3 consists of the sequence of SEQ ID NO: 79; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 62, VHCDR2 consists of the sequence of SEQ ID NO: 63, VHCDR3 consists of the sequence of SEQ ID NO: 64, VLCDR1 consists of the sequence of SEQ ID NO: 80, VLCDR2 consists of the sequence of SEQ ID NO: 78, and VLCDR3 consists of the sequence of SEQ ID NO: 81; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 65, VHCDR2 consists of the sequence of SEQ ID NO: 66, VHCDR3 consists of the sequence of SEQ ID NO: 67, VLCDR1 consists of the sequence of SEQ ID NO: 82, VLCDR2 consists of the sequence of SEQ ID NO: 83, and VLCDR3 consists of the sequence of SEQ ID NO: 84; or wherein:- VHCDR1 consists of the sequence of SEQ ID NO: 68, VHCDR2 consists of the sequence of SEQ ID NO: 69, VHCDR3 consists of the sequence of SEQ ID NO: 70, VLCDR1 consists of the sequence of SEQ ID NO: 85, VLCDR2 consists of the sequence of SEQ ID NO: 86 and VLCDR3 consists of the sequence of SEQ ID NO: 87;wherein said VHCDRs and VLCDRs are defined according to Kabat.

6. The antibody for the use according to any one of claims 1 -5 wherein said antibody comprises:a. a heavy chain variable domain sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 33, SEQ ID NO: 168, SEQ ID NO: 32, SEQ ID NO: 34 to SEQ ID NO: 37 or SEQ ID NO: 88 to SEQ ID NO: 95; orb. a light chain variable domain sequence of the amino acid sequence selected from the group consisting of: SEQ ID NO: 39, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 38, SEQ ID NO: 40 to SEQ ID NO:43, or SEQ ID NO: 96 to SEQ ID NO: 103 ; orc. the heavy chain variable domain of (a) and the light chain variable domain of (b).

7. The antibody for the use according to any one of claims 1 -6 wherein said antibody comprises (a) a VH sequence of the amino acid sequence and (b) a VL sequence of the amino acid sequence, wherein:- VH consists of the sequence of SEQ ID NO: 33 and VL consists of the sequence of SEQ ID NO: 39; or wherein:- VH consists of the sequence of SEQ ID NO: 168 and VL consists of the sequence of SEQ ID NO: 171; or wherein:- VH consists of the sequence of SEQ ID NO: 1689 and VL consists of the sequence of SEQ ID NO: 172; or wherein:- VH consists of the sequence of SEQ ID NO: 170 and VL consists of the sequence of SEQ ID NO: 39; or wherein:- VH consists of the sequence of SEQ ID NO: 32 and VL consists of the sequence of SEQ ID NO: 38; or wherein:- VH consists of the sequence of SEQ ID NO: 34 and VL consists of the sequence of SEQ ID NO: 40; or wherein:- VH consists of the sequence of SEQ ID NO: 35 and VL consists of the sequence of SEQ ID NO: 41; or wherein:- VH consists of the sequence of SEQ ID NO: 36 and VL consists of the sequence of SEQ ID NO: 42; or wherein:- VH consists of the sequence of SEQ ID NO: 37 and VL consists of the sequence of SEQ ID NO: 43; or wherein:- VH consists of the sequence of SEQ ID NO: 88 and VL consists of the sequence of SEQ ID NO: 96; or wherein:- VH consists of the sequence of SEQ ID NO: 88 and VL consists of the sequence of SEQ ID NO: 97; or wherein:- VH consists of the sequence of SEQ ID NO: 88 and VL consists of the sequence of SEQ ID NO: 98; or wherein:- VH consists of the sequence of SEQ ID NO: 91 and VL consists of the sequence of SEQ ID NO: 99; or wherein:- VH consists of the sequence of SEQ ID NO: 88 and VL consists of the sequence of SEQ ID NO: 100; or wherein:- VH consists of the sequence of SEQ ID NO: 93 and VL consists of the sequence of SEQ ID NO: 101; or wherein:- VH consists of the sequence of SEQ ID NO: 94 and VL consists of the sequence of SEQ ID NO: 102; or wherein:- VH consists of the sequence of SEQ ID NO: 95 and VL consists of the sequence of SEQ ID NO: 103.

8. The antibody for the use according to any one of claims 1 -7 wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 45 and the nucleotide sequence encoding VL comprises SEQ ID NO: 51; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 174 and the nucleotide sequence encoding VL comprises SEQ ID NO: 177; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 175 and the nucleotide sequence encoding VL comprises SEQ ID NO: 178 or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 176 and the nucleotide sequence encoding VL comprises SEQ ID NO: 179 or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 44 and the nucleotide sequence encoding VL comprises SEQ ID NO: 50; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 46 and the nucleotide sequence encoding VL comprises SEQ ID NO: 52; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 47 and the nucleotide sequence encoding VL comprises SEQ ID NO: 53; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 48 and the nucleotide sequence encoding VL comprises SEQ ID NO: 54; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 49 and the nucleotide sequence encoding VL comprises SEQ ID NO: 55; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 104 and the nucleotide sequence encoding VL comprises SEQ ID NO: 112; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 105 and the nucleotide sequence encoding VL comprises SEQ ID NO: 113; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 106 and the nucleotide sequence encoding VL comprises SEQ ID NO: 114; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 107 and the nucleotide sequence encoding VL comprises SEQ ID NO: 115; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 108 and the nucleotide sequence encoding VL comprises SEQ ID NO: 116; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 109 and the nucleotide sequence encoding VL comprises SEQ ID NO: 117; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 110 and the nucleotide sequence encoding VL comprises SEQ ID NO: 118; or wherein:- the nucleotide sequence encoding VH comprises SEQ ID NO: 111 and the nucleotide sequence encoding VL comprises SEQ ID NO: 119.

9. The antibody for the use according to any one of claims 1 -8 wherein said antibody is a human or a humanized antibody and / or is an IgG 1 or lgG2 or lgG4 antibody, preferably an lgG1 kappa antibody, an lgG1 lambda antibody, an lgG2 kappa antibody, an lgG2 lambda antibody, an lgG4 kappa antibody or an lgG4 lambda antibody.

10. The antibody for the use according to claim 9 wherein said lgG1 antibody comprises at least one amino-acid substitution in the heavy chain constant region (Fc) of the lgG1 antibody, wherein:- the at least one amino acid substitution is capable of reducing Fc receptor binding; or wherein- the at least one amino acid substitution is capable of reducing effector cell function of the antibody; or wherein- the at least one amino acid substitution is capable of extending the halflife of the antibody.

11. The antibody for the use according to claim 10 wherein the at least one amino acid substitution capable of extending the half-life of the antibody is selected from the following group: M252Y, S254T or T256E, where the numbering of the residues is according to the EU numbering system.

12. The antibody for the use according to any one of claims 1-11, wherein said antibody comprises:- a light chain comprising a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NO: 39, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 38, SEQ ID NO: 40 to SEQ ID NO: 43, or SEQ ID NO: 96to SEQ ID NO: 103; and a light constant domain comprising or consisting of a sequence of SEQ ID NO: 123 and / or- a heavy chain comprising a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NO: 33, SEQ ID NO: 168, SEQ ID NO: 32, SEQ ID NO: 34 to SEQ ID NO: 37, SEQ ID NO: 88, SEQ ID NO: 91, or SEQ ID NO: 93 to SEQ ID NO: 95; and a heavy chain constant domain comprising or consisting of a sequence of SEQ ID NO: 120 or of SEQ ID NO: 180.

13. The antibody for the use according to any one of claims 1-12, wherein said antibody comprises:- a light chain comprising a light chain variable domain comprising or consisting of a sequence of SEQ ID NO: 39 and a light chain constant domain comprising or consisting of a sequence of SEQ ID NO: 123 and / or- a heavy chain comprising a heavy chain variable domain comprising or consisting of a sequence of SEQ ID NO: 33 and a heavy chain constant domain comprising or consisting of a sequence of SEQ ID NO: 120 or of SEQ ID NO: 180;preferably wherein said antibody comprises a light chain comprising or consisting of a sequence of SEQ ID NO: 4 and / or a heavy chain comprising or consisting of a sequence of SEQ ID NO: 125 or of SEQ ID NO: 126.

14. An isolated polynucleotide comprising at least one sequence that encodes the antibody or antigen binding fragment thereof as disclosed in any one of claims 1-11, preferably said polynucleotide being a cDNA, or a vector comprising said polynucleotide, preferably said vector being selected from the group consisting of a plasmid, a viral vector, a non-episomal mammalian vector, an expression vector and a recombinant expression vector, or an isolated cell comprising said polynucleotide or said vector, preferably said isolated cell being a hybridoma or a Chinese Hamster Ovary (CHO) cell or a Human Embryonic Kidney cell (HEK293), for use in the prevention and / or treatment of colorectal cancer.

15. A pharmaceutical composition comprising an antibody that binds to TMEM219 receptor or an antigen-binding fragment thereof as disclosed in any one of claims 1-13 and at least one pharmaceutically acceptable carrier for use in theprevention and / or treatment of colorectal cancer, and / or reduction of risk of developing colorectal cancer in patients with inflammatory bowel disease (IBD).

16. The pharmaceutical composition according to claim 15 further comprising a second therapeutic agent.5      17. The antibody for use according to any one of claims 1-13 wherein said antibodyis used in combination with at least one further therapeutic agent.

18. The antibody for use according to claim 11 or the pharmaceutical composition for use according to claim 16 wherein said therapeutic agent is an active ingredient which is known to be effective in the prevention and / or treatment of cancer, 10         preferably of colorectal cancer, such as a chemotherapeutic agent or aradiotherapy agent, preferably said therapeutic agent is selected from fluoropyrimidine, oxaliplatin, irinotecan, leucovorin, capecitabine, anti-VEGF monoclonal antibodies or anti-VEGF small molecules, such as bevacizumab or aflibercept, cetuximab or panitumumab, ramucirumab, BRAF-inhibitors, such as 15         encorafenib, 5-aminosalicylic acid, immunomodulators, such as thiopurines, andimmune checkpoint inhibitors, such as pembrolizumab.

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