Humanized CLDN18.2 antibody

Abstract

The present invention provides humanized antibodies that bind to CLDN18.2 with high affinity. Furthermore, the antibodies do not exhibit cross-reactivity to CLDN18.1. The present invention also provides nucleic acids, vectors, host cells, and medical uses.

Description

Background Art

[0001] Tight junctions are multiprotein complexes that connect adjacent epithelial or endothelial cells to form a barrier, preventing the passage of molecules between cells and helping to maintain cell and tissue polarity. Tight junctions are composed of three major transmembrane proteins: claudin and occludin, cytoplasmic plaque proteins, and cingulin. They also contain cytoskeletal and signaling proteins such as actin, myosin II, and PKCζ. These proteins interact to maintain the tight junction structure (Yu and Turner 2008).

[0002] Claudin proteins form a family of 23 proteins (Hewitt, Agarwal, and Morin 2006). Claudin 18 is a human protein encoded by the CLDN18 gene that forms tight junction chains in epithelial cells. Human CLDN18 can undergo alternative splicing with two alternative first exons, resulting in two protein isoforms, CLDN18.1 (or claudin 18.1) and CLDN18.2 (or claudin 18.2). CLDN18.2 was first disclosed as the Zsig28 protein in WO2000 / 015659. These two isoforms differ in the N-terminal 69 amino acids encompassing the first extracellular loop. The first extracellular domain spans amino acids 28 to 80. Within this region, there are eight amino acid differences between CLDN18.1 and CLDN18.2. These two different isoforms are expressed in different tissues, with CLDN18.1 primarily expressed in lung tissue, while CLDN18.2 appears to be gastric-specific (Niimi et al. 2001). In normal stomach, CLDN18.2 expression is restricted to differentiated, short-lived cells of the gastric epithelium. CLDN18.2 expression has been identified in a variety of tumor tissues. For example, CLDN18.2 has been found to be expressed in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histological subtypes (Sahin et al. 2008).

[0003] Given the restricted expression pattern of CLDN18.2 in normal tissues and its ectopic expression in human cancers, CLDN18.2 is an attractive pan-cancer target for antibody therapy of epithelial tumors. Many studies have been conducted on this antibody therapy. WO2004 / 047863 identified splice variants of CLDN18 and screened antibodies against the following different peptides derived from CLDN18.2: peptide DQWSTQDLYN (SEQ ID NO: 68), the N-terminal extracellular domain of CLDN18.2, independent of glycosylation; peptide NNPVTAVFNYQ (SEQ ID NO: 69), the N-terminal extracellular domain of CLDN18.2, which is predominantly unglycosylated; and peptide STQDLYNNPVTAVF (SEQ ID NO: 70), the N-terminal extracellular domain of CLDN18.2, which is unglycosylated. It also discloses polyclonal rabbit antibodies screened with the pan-CLDN18 peptide TNFWMSTANMYTG (SEQ ID NO: 71) in the C-terminal extracellular domain common to CLDN18.1 and CLDN18.2 isoforms. WO2005 / 113587 discloses antibodies directed against specific epitopes on CLDN18.2 defined by the following peptide sequences: ALMIVGIVLGAIGLLV (SEQ ID NO: 72) and RIGSMEDSAKANMTLTSGIMFIVS (SEQ ID NO: 73). WO200 / 7059997 discloses a CLDN18.2-specific monoclonal antibody obtained by immunization with the peptide METDTLLLWWVLLLWVPGSTGDAAQPARRARRTKLGTELGSTPVWWNSADGRMDQWSTQDLYNNPVTAVFNYQGLWRSCRESSGFTECRGYFTLLGLPAMLQAVRAAIQHSGGRSRARTKTHLRRGSE (SEQ ID NO: 74) (including the first extracellular domain of CLDN18.2 with N-terminal and C-terminal extensions). The antibody obtained by this immunization mediates cell killing through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Antibody IMAB362, also known as Claudiximab or Zolbetuximab, is disclosed in WO2007 / 059997 and WO2016 / 165762. IMAB362 is an IgG1 antibody derived from a mouse monoclonal antibody and chimerized to display human IgG1 constant regions for clinical use.WO2008 / 145338 also discloses antibodies that bind to overlapping peptides within the first extracellular domain (MDQWSTQDLYNNPVT (SEQ ID NO: 75), LYNNPVTAVFNYQGL (SEQ ID NO: 76), VFNYQGLWRSCVRESS (SEQ ID NO: 77), QGLWRSCVT (SEQ ID NO: 78), and RSCVRESSGFTECRG (SEQ ID NO: 79)). To generate antibodies targeting the C-terminal portion of CLDN18.2 for diagnostic purposes to detect CLDN18.2 expression in cells of cancer tissue sections, WO2013 / 167259 discloses antibodies that bind to a C-terminal epitope of CLDN18.2. The sequences of the two epitopes are TEDEVQSYPSKHDYV (SEQ ID NO: 80) and EVQSYPSKHDYV (SEQ ID NO: 81). WO2013 / 174509 proposes a combination of an anti-CLDN18.2 antibody and an agent that stabilizes γδ T cells or an agent that stabilizes or increases CLDN18.2 expression. The antibody can be conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant), or a radioisotope. WO2014075788 discloses a method for treating cancer using a bispecific antibody that binds to CLDN18.2 and CD3. WO2014 / 127906 discloses a combination agent that stabilizes or increases CLDN18.2 expression. WO2016 / 166122 discloses an anti-CLDN18.2 monoclonal antibody that can be efficiently internalized upon binding to CLDN18.2 and is therefore suitable for the development of antibody-drug conjugates (ADCs). Furthermore, conjugation of these antibodies to the drugs DM4 and MMAE using cleavable SPDB or valine-citrulline linkers, respectively, is disclosed. However, despite all the antibodies disclosed in the patent applications, only the chimeric IMAB362 disclosed in WO2007 / 059997 and WO2016 / 165762 is currently being tested in clinical trials. In addition to these antibodies and ADCs, WO2018 / 006882 discloses chimeric antigen receptors (CARs) based on anti-CLDN18.2 monoclonal antibodies. The antibodies in WO2018 / 006882 have been humanized, and their sequences are disclosed in the supplementary materials section associated with Jiang et al. (2018). CAR T cells based on humanized antibodies are currently being tested in a Phase I clinical trial in patients with advanced gastric and pancreatic adenocarcinoma (ClinicalTrials.gov identifier: NCT03159819). CN109762067 discloses other anti-CLDN18.2 monoclonal antibodies that mediate cell killing via CDC and ADCC. WO2019 / 173420 discloses an anti-CLDN18.2 humanized monoclonal antibody with ADCC activity.WO2019 / 175617 discloses anti-CLDN18.2 monoclonal antibodies that bind to different epitopes than IMAB362. WO2019 / 219089 discloses monoclonal antibodies that bind to mutants of CLDN18.2.

[0004] Chimeric antibodies, which have mouse variable regions grafted onto human constant domains, are often still immunogenic, potentially leading to enhanced clearance and other safety concerns (Sauerborn 2014). Therefore, further modification of antibody sequences is needed to reduce patient immune responses and improve therapeutic activity. Humanization is the process of modifying the sequence of a xenogeneic antibody to reduce this immunogenicity (Sauerborn 2014). However, humanization of antibodies often also results in a loss of affinity. IMAB362, currently the most advanced anti-CLDN18.2 antibody in clinical use, is a chimeric antibody. Therefore, there remains a need for better anti-CLDN18.2 antibodies. The present invention addresses these and other needs by disclosing a humanized IMAB362 antibody with a surprisingly higher affinity for CLDN18.2 than IMAB362. Summary of the Invention

[0005] definition

[0006] "Antibodies" or "antibodies", also known as "immunoglobulins" (Ig), typically comprise four polypeptide chains, two heavy (H) chains and two light (L) chains, and are therefore multimeric proteins, or comprise equivalent Ig homologs thereof (e.g., camelid antibodies, single domain antibodies (sdAbs), or nanobodies derived from heavy or light chains comprising only heavy chains). The term "antibody" includes antibody-based binding proteins, modified antibody forms that retain their target binding ability. The term "antibody" also includes full-length functional mutants, variants, or derivatives thereof (including but not limited to murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies) that retain the basic epitope binding characteristics of Ig molecules, and includes dual-specific, bispecific, multispecific, and dual variable domain Igs. Ig molecules can be of any class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) and allotype. Ig molecules may also undergo mutations that, for example, increase or decrease affinity for Fcγ receptors or neonatal Fc receptor (FcRn).

[0007] As used herein, "antibody fragment" refers to a molecule comprising at least one polypeptide chain derived from an antibody that is not full-length and that exhibits target binding, including but not limited to (i) a Fab fragment, which is a monovalent fragment consisting of a variable light (VL), a variable heavy (VH), a constant light (CL), and a constant heavy 1 (CH1) domain; (ii) a F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region (reduction of the F(ab')2 fragment results in two Fab' fragments with free sulfhydryl groups); (iii) the heavy chain portion of a Fab (Fa) fragment, which consists of the VH and CH1 domains; (iv) a variable fragment (Fv) fragment, which consists of the VL and VH domains of a single arm of an antibody; (v) a domain antibody (dAb) fragment, which comprises Containing a single variable domain; (vi) isolated complementarity determining regions (CDRs); (vii) single-chain Fv fragments (scFv); (viii) diabodies, which are bivalent bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but the linker used is too short to allow pairing between the two domains on the same chain, thereby forcing the domains to pair with the complementary domains of another chain and create two antigen-binding sites; (ix) linear antibodies, which include a pair of tandem Fv fragments (VH-CH1-VH-CH1) that, together with complementary light chain polypeptides, form a pair of antigen-binding regions; (x) dual variable domain immunoglobulins (xi) other non-full-length portions of immunoglobulin heavy and / or light chains, or mutants, variants, or derivatives thereof, alone or in any combination.

[0008] As used herein, "antibody-based binding protein" may refer to any protein comprising at least one antibody-derived VH, VL, or CH immunoglobulin domain in the context of other non-immunoglobulin or non-antibody-derived components. Such antibody-based proteins include, but are not limited to, (i) FC-fusion proteins of binding proteins, including receptors or receptor components having all or part of an immunoglobulin CH domain, (ii) binding proteins in which the VH and / or VL domains are coupled to a variable molecular scaffold, or (iii) molecules in which immunoglobulin VH and / or VL and / or CH domains are combined and / or assembled in a manner not normally found in naturally occurring antibodies or antibody fragments.

[0009] As used herein, the term "modified antibody formats" includes polyalkylene oxide-modified scFvs, monobodies, diabodies, camelid antibodies, domain antibodies, bispecific or trispecific antibodies, IgA or two IgG structures connected by a J chain and secretory component, shark antibodies, New World primate frameworks and non-New World primate CDRs, IgG4 antibodies with the hinge region removed, IgG with two additional binding sites engineered into the CH3 domain, antibodies with altered Fc regions to increase or decrease affinity for Fcγ receptors, dimerization constructs comprising CH3, VL and VH, and the like.

[0010] The Kabat numbering scheme (Martin and Allemn 2014) has been applied to the disclosed antibodies.

[0011] As used herein, the term "selectively binds to CLDN18.2" or "selectively binds to CLDN18.2" refers to an antibody that binds to CLDN18.2 but does not (specifically) bind to CLDN18.1. Thus, an antibody that selectively binds to CLDN18.2 does not exhibit cross-reactivity with CLDN18.1.

[0012] When the term "comprising" is used in the present description and claims, it does not exclude other elements. For the purposes of the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising". If a group is defined below as comprising at least a certain number of embodiments, this should also be understood to disclose a group that preferably consists only of these embodiments.

[0013] Where an indefinite or definite article is used when referring to a singular noun, for example "a", "an" or "the", this includes a plural of that noun unless something else is specifically stated.

[0014] Technical terms are used according to their common sense. If specific meanings are conveyed to certain terms, the definitions of the terms will be given below in the context in which the terms are used.

[0015] describe

[0016] The inventors have surprisingly identified novel anti-CLDN18.2 antibodies, as further described in the embodiments below. These antibodies bind to CLDN18.2 with a higher affinity than the IMAB362 antibody.

[0017] Thus, in one embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, comprising the heavy chain complementary determining region (HCDR) HCDR1, HCDR2, and HCR3 consensus sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the light chain complementary region (LCDR) LCDR1, LCDR2, and LCDR3 consensus sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. The respective consensus sequences can be found in Table 1. It is understood that any antibody or fragment thereof that binds to CLDN18.2 based on any combination of CDRs derived from the consensus sequence is part of the present invention.

[0018] In a preferred embodiment, the isolated antibody or functional fragment thereof binds to CLDN18.2 but does not bind to CLDN18.1. Thus, the provided antibody specifically binds to CLDN18.2.

[0019] Table 1: Isolated antibody CDR consensus sequences

[0020]

[0021]

[0022] Antibody binding or binding affinity is often expressed in terms of equilibrium association or dissociation constants (K a or K d ), the equilibrium association or dissociation constants are the dissociation rate constant and the association rate constant (k off and k on ). Thus, equivalent affinities may correspond to different rate constants as long as the ratio of rate constants remains constant. Binding affinity and / or rate constants can be determined using techniques known in the art or described herein, such as ELISA, flow cytometry (FC) titration, isothermal titration calorimetry (ITC), Biacore (SPR), biolayer inferometry, or fluorescence polarization. In some cases, due to the nature of the antigen, the K of the antibody may be different from that of the antigen. a or K d Can be difficult to measure. This is especially true for integral membrane proteins such as claudin (Hashimoto et al. 2018). In this case, the integral membrane protein can be expressed as proteoliposomes or lipid particles. Such lipid particles can be immobilized on plastic and used in ELISA assays to determine the binding affinity of the antibody to the immobilized antigen. Instead of K a or Kd Values can be used to calculate a half-maximal effective concentration (EC50) value for each test antibody or its functional fragment, reflecting its binding affinity to the antigen. Example 3 and Figure 2 below illustrate ELISA binding affinity curves for antibodies to the CDRs contained in the consensus sequence of Table 1. Therefore, binding can be determined according to Example 4, where the EC50 value (Table 4 in Example 4) and the upper curve value (Figure 4) are used for quantification. The EC50 value and the upper curve value (maxMFI) surprisingly show that the humanized antibodies of the present invention have higher binding affinity, that is, they show enhanced binding to CLDN18.2 compared to the IMAB362 antibody. The maximum mean fluorescence intensity (maxMFI) can also be used to quantify antibody binding. When comparing two antibodies binding to the same target, a higher maxMFI indicates a higher affinity and / or a lower dissociation rate. When binding is measured by FC on HEK293T cells or PA-TU-8988S-high cells expressing CLDN18.2, the maxMFI can be determined as described in Example 4, and the maxMFI values for the antibodies of the present invention are shown in Table 4.

[0023] Therefore, it is preferred that the antibodies or fragments thereof of the present invention bind to CLDN18.2 with a higher affinity than the IMAB362 antibody. Conversely, Figure 1D shows that all antibodies tested did not bind to HEK293T cells expressing CLDN18.1, and accordingly, all antibodies tested selectively bound to CLDN18.2. Furthermore, in a preferred embodiment, such antibodies or fragments thereof are humanized.

[0024] In another embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, comprising:

[0025] a. HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 18, respectively, and LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5, and SEQ ID NO: 29, respectively;

[0026] b. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 19, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0027] c. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 20, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 30, respectively;

[0028] d. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 12 and SEQ ID NO: 21, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 26, SEQ ID NO: 5 and SEQ ID NO: 30, respectively;

[0029] e. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 13 and SEQ ID NO: 18, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 31, respectively;

[0030] f. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 14 and SEQ ID NO: 22, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0031] g. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 15 and SEQ ID NO: 23, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 27, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0032] h. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 16 and SEQ ID NO: 23, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; or

[0033] i. The HCDR1, HCDR2 and HCDR3 sequences are SEQ ID NO: 8, SEQ ID NO: 17 and SEQ ID NO: 24, respectively, and the LCDR1, LCDR2 and LCDR3 sequences are SEQ ID NO: 28, SEQ ID NO: 5 and SEQ ID NO: 31, respectively.

[0034] In preferred embodiments, the antibodies are humanized. As described above, these novel humanized antibodies bind to CLDN18.2 with a higher affinity than the IMAB362 antibody, as shown, for example, by EC50 and maxMFI values. Furthermore, the provided antibodies selectively bind to CLDN18.2.

[0035] In another embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, comprising:

[0036] a. VH sequence of SEQ ID NO: 32;

[0037] b. VH sequence of SEQ ID NO: 34;

[0038] c. VH sequence of SEQ ID NO: 35;

[0039] d. VH sequence of SEQ ID NO: 37;

[0040] e. VH sequence of SEQ ID NO: 39;

[0041] f. VH sequence of SEQ ID NO: 41;

[0042] g. VH sequence of SEQ ID NO: 42;

[0043] h. the VH sequence of SEQ ID NO: 44; or

[0044] i. VH sequence of SEQ ID NO: 45;

[0045] and

[0046] j. VL sequence of SEQ ID NO: 33;

[0047] k. VL sequence of SEQ ID NO: 36;

[0048] 1. VL sequence of SEQ ID NO: 38;

[0049] m. VL sequence of SEQ ID NO: 40;

[0050] n. the VL sequence of SEQ ID NO: 43; or

[0051] o. VL sequence of SEQ ID NO:46.

[0052] In preferred embodiments, the antibodies are humanized. As described above, these novel humanized antibodies bind to CLDN18.2 with higher affinity than the IMAB362 antibody, as shown, for example, by EC50 and maxMFI values. Furthermore, the provided antibodies selectively bind to CLDN18.2. It is understood that any isolated antibody or fragment thereof that binds to CLDN18.2 based on any combination of VH and VL regions is part of the present invention. In preferred embodiments, the antibody or functional fragment thereof binds to CLDN18.2 but not to CLDN18.1.

[0053] In another embodiment, the present invention relates to an antibody or fragment thereof that binds to CLDN18.2, comprising:

[0054] a. VH sequence of SEQ ID NO: 32 and VL sequence of SEQ ID NO: 33;

[0055] b. VH sequence of SEQ ID NO: 34 and VL sequence of SEQ ID NO: 33;

[0056] c. VH sequence of SEQ ID NO: 35 and VL sequence of SEQ ID NO: 36

[0057] d. VH sequence of SEQ ID NO: 37 and VL sequence of SEQ ID NO: 38;

[0058] e. VH sequence of SEQ ID NO: 39 and VL sequence of SEQ ID NO: 40;

[0059] f. VH sequence of SEQ ID NO:41 and VL sequence of SEQ ID NO:33;

[0060] g. VH sequence of SEQ ID NO: 42 and VL sequence of SEQ ID NO: 43;

[0061] h. the VH sequence of SEQ ID NO: 44 and the VL sequence of SEQ ID NO: 33; or

[0062] i. VH sequence of SEQ ID NO:45 and VL sequence of SEQ ID NO:46.

[0063] In preferred embodiments, the antibodies are humanized. Also, as described above, these novel humanized antibodies bind to CLDN18.2 with a higher affinity than the IMAB362 antibody, as shown, for example, by EC50 and maxMFI values. Furthermore, the provided antibodies selectively bind to CLDN18.2.

[0064] In another embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, consisting of:

[0065] a. the heavy chain sequence of SEQ ID NO: 49 and the light chain sequence of SEQ ID NO: 50;

[0066] b. the heavy chain sequence of SEQ ID NO: 51 and the light chain sequence of SEQ ID NO: 50;

[0067] c. the heavy chain sequence of SEQ ID NO: 52 and the light chain sequence of SEQ ID NO: 53;

[0068] d. the heavy chain sequence of SEQ ID NO: 54 and the light chain sequence of SEQ ID NO: 55;

[0069] e. the heavy chain sequence of SEQ ID NO: 56 and the light chain sequence of SEQ ID NO: 57;

[0070] f. the heavy chain sequence of SEQ ID NO: 58 and the light chain sequence of SEQ ID NO: 50;

[0071] g. the heavy chain sequence of SEQ ID NO: 59 and the light chain sequence of SEQ ID NO: 60;

[0072] h. the heavy chain sequence of SEQ ID NO: 61 and the light chain sequence of SEQ ID NO: 50; or

[0073] i. The heavy chain sequence of SEQ ID NO: 62 and the light chain sequence of SEQ ID NO: 63.

[0074] In preferred embodiments, the antibodies are humanized. Also, as described above, these novel humanized antibodies bind to CLDN18.2 with a higher affinity than the IMAB362 antibody, as shown, for example, by EC50 and maxMFI values. Furthermore, the provided antibodies selectively bind to CLDN18.2.

[0075] In another embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, wherein the antibody or fragment thereof is humanized. The humanization of monoclonal antibodies is well established. The second edition of the Handbook of Therapeutic Antibodies provides extensive information on the humanization of monoclonal antibodies (Saldanha 2014), bioinformatics tools for analyzing such antibodies (Martin and Allemn 2014), and the development and manufacture of therapeutic antibodies (Jacobi et al. 2014). When used as human therapeutics, humanized antibodies have a lower risk of inducing anti-drug antibodies than chimeric antibodies, which would limit the therapeutic benefit of the antibodies of the present invention and increase the risk of side effects, especially after repeated administration.

[0076] In another embodiment, the present invention provides an isolated antibody or a functional fragment thereof that binds to CLDN18.2.

[0077] In one embodiment, the antibody of the invention does not bind to CLDN18.1. Therefore, it does not exhibit cross-reactivity.

[0078] In another embodiment, the present invention provides an antibody or a functional fragment thereof that binds to CLDN18.2, consisting of a heavy chain sequence of SEQ ID NO: 58 and a light chain sequence of SEQ ID NO: 50.

[0079] In another embodiment, the invention relates to an antibody having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of an antibody described herein. Preferably, the antibody binds to CLDN18.2 with a higher affinity, e.g., as shown by EC50 and maxMFI values, and / or selectively binds to CLDN18.2, compared to the IMAB362 antibody. In one embodiment, the antibody is humanized.

[0080] In one embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2 and competes for binding with an antibody or fragment thereof described herein. In a preferred embodiment, the antibody or fragment thereof competes for binding with an antibody consisting of the heavy chain sequence of SEQ ID NO: 58 and the light chain sequence of SEQ ID NO: 50. In one embodiment, the antibody is humanized. In a further preferred embodiment, the antibody exhibits a binding affinity that is the same as or increased compared to that of IMAB362. In another preferred embodiment, the antibody exhibits a binding affinity that is the same as or increased compared to that of an antibody consisting of the heavy chain sequence of SEQ ID NO: 58 and the light chain sequence of SEQ ID NO: 50. Binding affinity can be measured by any suitable method. For example, antibody binding can be measured by EC50 value or maxMFI using flow cytometry titration on HEK295T cells or PA-TU-8988-high cells expressing CLDN18.2.

[0081] In another embodiment, the Fc domain of the antibody (or antibody fragment, when present) may include modifications or mutations, such as those listed in Table 2 below. Such modifications or mutations may be introduced to modulate the effector activity of the antibody Fc domain. Antibody modifications may also include peptide tags added to the C-terminus of the antibody HC and / or LC chains. Such tags may be used, for example, for protein purification or protein conjugation.

[0082] In another embodiment, the present invention provides an isolated humanized antibody or fragment thereof that binds to CLDN18.2, wherein the antibody is in the form of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, synthetic IgG, IgM, F(ab)2, Fv, scFv, IgGACH2, F(ab')2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, non-depleted IgG, diabody, bivalent antibody, or Fc-engineered version thereof.

[0083] In a preferred embodiment, antibody is IgG1 type antibody.The Fc region of immunoglobulin interacts with a variety of Fc γ receptors (Fc γ R) and complement proteins (such as C1q), mediates immune effector functions, such as eliminating targeted cells by antibody-dependent cellular toxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC).For therapeutic methods, enhancing or silencing Fc-related effector functions may be beneficial.The type of immunoglobulin (IgA, IgD, IgE, IgG, IgM) can be selected according to the desired effector function of the antibody related to the Fc domain, in view of their known activity.Synthetic immunoglobulin can also be used, such as the immunoglobulin with IgG2 amino acid 118 to 260 and IgG4 amino acid 261 to 447 or the IgG2 variant with point mutation (for example, H268Q / V309L / A30S / P331S) from IgG4.The immunoglobulin of this synthesis reduces the effector function of antibody. Fc-engineered immunoglobulins can also be used to modulate antibody effector functions. Examples of such Fc engineering are shown in Table 2. Expression in production cell lines with altered fucosylation may also affect FCγR binding, thereby modulating the pharmacokinetics of the antibody.

[0084] Table 2 : Examples of modifications that modulate antibody effector function. Unless otherwise indicated, mutations are on the IgG1 subclass (Wang, Mathieu, and Brezski 2018).

[0085]

[0086]

[0087]

[0088] The in vivo half-life of antibodies can also be regulated. The Fc domain plays a central role in the stability and serum half-life of antibodies. For therapeutic methods, antibody half-life can be reduced by using antibody fragments lacking the Fc domain or having the Fc domain of a truncation, such as F(ab)2, Fv, scFv, IgGACH2, F(ab')2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc or (scFv)2. Antibodies can also be in the form of double antibodies or bivalent antibodies. Double antibodies or bivalent antibodies can be used to increase affinity for the target, to allow for reduced dosage. Functional fragments lacking the Fc domain or having the Fc domain of a truncation can also be used for other therapeutic methods, such as the development of chimeric antigen receptor T cells (CAR T cells) or bispecific T cell genes (BiTE). In CAR constructs, a VH and a VL domain are typically linked by a short peptide linker to form a single-chain variable fragment (scFv), which is further linked to a transmembrane domain and a cytoplasmic T cell immunoreceptor tyrosine-based activation motif (e.g., from CD3ζ), as well as other domains of costimulatory molecules (e.g., from CD28, 4-1BB (CD127), or OX40) (Chang and Chen 2017). The VH and VL domains used in the scFv fragment may be the antibodies listed in Table 3. BiTEs typically consist of two scFv fusions of two different antibodies. One scFv domain may be an isolated antibody that binds to CLDN18.2, as listed in Table 3, while the other scFv domain may be derived from an antibody that binds to, for example, CD3, CD16, NKG2D, NKp46, CD2, CD28, or CD25. A comprehensive guide to BiTE antibody formats and other diabody formats for T cell redirection can be found in the review by Diego Ellerman (2019).

[0089] In another embodiment, the present invention provides a humanized antibody or fragment thereof that binds to CLDN18.2, the antibody having a constant light chain region (CL) of SEQ ID NO: 65 and preferably a constant heavy chain region CH1 and Fc region of SEQ ID NO: 66, which has reduced FcγR binding and has L234A / L235A mutations in the constant heavy chain region CH2. More preferably, the present invention provides an antibody having a constant heavy chain region CH1 and Fc region of SEQ ID NO: 67, which has L234A / L235A / P329G mutations in the constant heavy chain region CH1 and Fc region, which even further reduces FcγR binding.

[0090] In another embodiment, the present invention provides an isolated humanized antibody or fragment thereof that binds to CLDN18.2, has a VH sequence of SEQ ID NO: 41 associated with a constant heavy chain region CH1 and Fc region of SEQ ID NO: 66, and a VL sequence of SEQ ID NO: 33 associated with a constant light chain region (CL) having SEQ ID NO: 65.

[0091] In another embodiment, the present invention provides antibodies or fragments thereof that bind to CLDN18.2, wherein the antibodies or fragments thereof do not bind to CLDN18.1. Thus, the antibodies do not exhibit cross-reactivity or cross-binding with CLDN18.1. Binding of the antibody to the target protein can be tested by flow cytometry on cells expressing the target protein. Specific binding of the test antibody to its target protein can be displayed in a histogram. When the antibody specifically binds to the expressed target protein, such a graph results in a peak with a high fluorescent signal, while when the antibody does not bind to the expressed target protein or binds only very weakly to the expressed target protein, such a graph results in a peak with a low fluorescent signal. Such a histogram can be seen in Figure 1, which shows binding of an antibody of the present invention to CLDN18.2 expressed in HEK293T cells, but not to CLDN18.1. The extent of binding can also be represented by a bar graph showing the maximum mean fluorescence intensity (maxMFI) measured by flow cytometry, with a high maxMFI reflecting strong binding and a low / no maxMFI reflecting no binding. An example of such a binding assay can be found in Example 4.

[0092] In another embodiment, the present invention provides an antibody or fragment thereof that binds to CLDN18.2, wherein the antibody is conjugated to another moiety. This moiety may include a radioisotope, a fluorescent label, a histological marker, a cytotoxin, or a cytokine. The binding of this moiety may be facilitated by a linker known in the art.

[0093] In another embodiment, the present invention provides antibodies or fragments that bind to CLDN18.2, wherein the antibodies or fragments thereof exhibit stronger binding to CLDN18.2 than the antibody IMAB362. Preferably, the present invention provides antibodies or fragments that bind to CLDN18.2, wherein the antibodies or fragments thereof bind to CLDN18.2 with a higher affinity than the IMAB362 antibody. Binding affinity and / or rate constants can be determined using techniques known in the art or described herein, such as ELISA, flow cytometry titration, isothermal titration calorimetry (ITC), Biacore (SPR), biolayer interferometry, or fluorescence polarization. The present inventors determined the affinity of antibodies for CLDN18.2 by ELISA as described in Example 3 or FC titration experiments as described in Example 4. In an ELISA on lipid particles containing CLDN18.2, the maximum binding values (expressed as MFI) of all humanized antibodies hGBA-1 to hGBA-9 were higher than that of IMAB362. In FC titration experiments using HEK293T cells overexpressing CLDN18.2 or PA-TU-8988S cells endogenously expressing CLDN18.2, all humanized antibodies hGBA-1 to hGBA-9 had higher maximum binding values (expressed in MFI units) and lower EC50 values (expressed in μg / ml) than antibody IMAB362, indicating that the humanized antibodies of the present invention have a higher affinity for CLDN18.2 than antibody IMAB362. In one embodiment, the measured EC50 value of the antibody provided herein is at least 10%, at least 20%, at least 40%, at least 50%, or at least 75% lower than the measured EC50 value of antibody IMAB362. In one embodiment, the antibody provided herein has a measured maxMFI value that is at least 10%, at least 20%, at least 40%, at least 50%, or at least 75% higher than the maxMFI value measured for antibody IMAB362.

[0094] The heavy and light chain sequences of the IMAB362 antibody are provided, for example, herein as SEQ ID NO: 47 and SEQ ID NO: 48.

[0095] According to one embodiment, the present invention provides nucleic acid sequences encoding antibodies or fragments thereof that bind to CLDN18.2. The nucleic acid sequence can encode individual CDRs, VH and VL regions, or the entire heavy and light chains of an antibody. These nucleic acid sequences can be found in Table 3. The nucleic acid sequence can also encode F(ab)2, Fv, scFv, IgGACH2, F(ab')2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, non-depleted IgG, diabodies, bivalent antibodies, or Fc-engineered versions thereof. The encoded immunoglobulin can be IgA1, IgA2, IgD, IgE, IgG1, IdG2, IgG3, IgG4, synthetic IgG, IgM, or mutant and Fc-engineered versions thereof.

[0096] In another embodiment, the present invention provides an antibody-based binding protein that binds to CLDN18.2, for example, a protein comprising at least the CLDN18.2 binding domain of a disclosed antibody and another protein domain unrelated to the antibody. The present invention also provides modified humanized antibody forms that bind to CLDN18.2. In a preferred embodiment, the antibody-based binding protein does not bind to CLDN18.1.

[0097] In another embodiment, the present invention provides a nucleic acid encoding an antibody or a fragment thereof. Such a nucleic acid sequence may further encode other elements and may be part of a chimeric antigen receptor (CAR) that binds to CLDN18.2. Adequate guidance on the construction of CAR T cells can be found in Chang and Chen (2017) or June and Sadelain (2018). In one embodiment, the present invention provides a T cell that has been genetically engineered to produce an artificial T cell receptor, wherein the artificial T cell receptor comprises an antibody of the present invention or a functional fragment thereof that binds to CLDN18.2. In a preferred embodiment, the CAR construct does not bind to CLDN18.1.

[0098] The present invention also provides expression vectors comprising such nucleic acids. The expression vectors can be directed to mammalian cells, bacteria, fungi, or insect cells, and the host cell type selected is suitable for carrying the expression vector comprising the nucleic acid encoding the antibody or its functional fragment. Adequate guidance for constructing such vectors can be found in Green and Sambrook (Green and Sambrook 2012). Expression vectors for mammalian cells, particularly CHO cells, are preferred.

[0099] In another embodiment, the present invention provides a host cell comprising an expression vector encoding an antibody or fragment thereof that binds to CLDN18.2, or a nucleic acid encoding an antibody or fragment thereof that binds to CLDN18.2 integrated into its genome. The host cell can be a mammalian cell or cell line, a bacterial, fungal, or insect cell. Mammalian cells are preferred, particularly CHO cells.

[0100] In another embodiment, the present invention relates to antibodies or fragments thereof that bind to CLDN18.2, nucleic acids encoding the antibodies or fragments thereof, vectors comprising the nucleic acids, or host cells comprising the nucleic acids or vectors comprising the nucleic acids, as described herein, for use in treating subjects having a neoplastic disease or at risk of developing a neoplastic disease, and / or for treating subjects diagnosed with a neoplastic disease. The disclosed antibodies or fragments thereof can be used as monotherapy or, preferably, as combination therapy with established standards of care for neoplastic diseases.

[0101] In another embodiment, the present invention provides use of an antibody or fragment thereof that binds to CLDN18.2 as provided herein in the preparation of a medicament for treating a neoplastic disease.

[0102] The neoplastic disease may be at least one disease selected from pancreatic cancer, gastric cancer, esophageal cancer, ovarian cancer, and lung cancer. It is understood that the neoplastic disease to be treated is characterized by overexpression of CLDN18.2.

[0103] Another embodiment of the present invention provides a method for treating a neoplastic disease using an isolated humanized antibody or fragment thereof that binds to CLDN18.2 as provided herein, wherein the neoplastic disease includes pancreatic cancer, gastric cancer, esophageal cancer, ovarian cancer, or lung cancer, wherein the method comprises administering a therapeutically effective amount of the antibody or fragment thereof. The treatment method can be monotherapy or, preferably, in combination with an established standard of care for the neoplastic disease.

[0104] Also provided is a pharmaceutical composition comprising an antibody or fragment thereof that binds to CLDN18.2, a nucleic acid encoding the antibody or fragment thereof, a vector comprising the nucleic acid, or a host cell comprising the nucleic acid or the vector comprising the nucleic acid, and a pharmaceutically acceptable carrier.

[0105] Preferably, patients with pancreatic, gastric, esophageal, ovarian, or lung cancer can be treated with an isolated humanized antibody or fragment thereof that binds to CLDN18.2, as provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1:FACS binding assay of humanized antibodies to IMAB362. Binding of selected antibodies to huCLDN1.2 and huCLDN18.1 was tested in HEK293T cells stably expressing huCLDN18.2 or huCLDN18.1. Parental HEK293T cells that do not express the target protein served as a negative control. 1A: A: IMAB362, B: hGBA-1, C: hGBA-2, D: hGBA-3, E: hGBA-4, F: hGBA-5, G: hGBA-6, H: hGBA-7, I: hGBA-8, J: GBA-9, K: secondary antibody alone, L: pan-CLDN18 antibody; 1B: Bar graph showing the mean fluorescence intensity (MFI) of FACS binding data for each humanized antibody compared to IMAB362 on parental HEK293T cells and HEK293T cells expressing huCLDN18.2 or huCLDN18.1.

[0107] Figure 2: 2A-D: ELISA binding assay of humanized antibodies compared to IMAB362. ELISA binding assays were performed on lipid particles carrying CLDN18.2 or empty lipid particles without CLDN18.2.

[0108] Figure 3: PA-TU-8988S cells were sorted for CLDN18.2 expression. 3A: FACS profile of PA-TU-9888S cells stained with IMAB362. 3B: FACS profile of PA-TU-8988S cells sorted by FACS for medium and high expression of CLDN18.2.

[0109] Figure 4: FC titration assays on PA-TU-8988S-high cells (4A-D) and HEK-293T cells expressing huCLDN18.2 (4E-H). Example

[0110] Example 1: Humanization of Fab fragments

[0111] The technology for humanizing monoclonal antibodies has been established for a long time. The second edition of the Handbook of Therapeutic Antibodies provides sufficient information on the humanization of monoclonal antibodies (Saldanha 2014), bioinformatics tools for the analysis of such antibodies (Martin and Allemn 2014), or the development and manufacture of therapeutic antibodies (Jacobi et al. 2014). Briefly, the variable domain sequences of the parental IMAB362 antibody were analyzed to reveal the closest human germline. Next, the variable regions of IMAB362 were structurally analyzed to reveal the best-fitting Fv model, followed by structural analysis of the CDR grafts by in silico modeling. Based on the in silico modeling, humanized VH and VL domains were designed. Combinations of humanized VH and VL domains were cloned and produced as Fab and IgG1 antibodies and assayed by ELISA and AlphaLISA. TM They were screened for binding to lipid particles expressing CLDN18.2 and for binding to pre-B cell L11 (Waldmeier et al. 2016) and HEK293T (ATCC CRL-3216) cell lines expressing CLDN18.1 and CLDN18.2 by flow cytometry. After testing and comparing with IMAB362, a VH and VL combination was selected and the library was designed in scFv format for further humanization including CDRs. TM The scFv library was screened against lipid particles expressing CLDN18.2 and by flow cytometry using the pre-B cell L11 cell line expressing CLDN18.1 and CLDN18.2. Thus, humanization of IMAB362 resulted in the humanized antibodies hGBA-1, hGBA-2, hGBA-3, hGBA-4, hGBA-5, hGBA-6, hGBA-7, hGBA-8, and hGBA-9 (see Table 3), collectively referred to herein as hGBA antibodies.

[0112] Table 3: Nucleic acid and amino acid sequences of selected antibodies

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] The antibodies described in Examples 2 to 4 were modified to contain an RLPXTGG tag (SEQ ID NO: 143) at the C-terminus of the HC and / or a GGGGSLPXTGG tag (SEQ ID NO: 144) at the C-terminus of the LC, where X is any of the 20 natural amino acids. In this case, the C-terminal lysine (K) on the HC was replaced with the arginine (R) of the tag. The addition of the tag did not alter the affinity and selectivity of the antibody for CLDN18.2.

[0123] Example 2: FACS binding analysis of humanized mAbs

[0124] The HEK293T (ATCC CRL-3216) cell line does not endogenously express CLDN18.1 or CLDN18.2. Therefore, to test antibody binding activity, CLDN18.1 and CLDN18.2 were overexpressed in the HEK293T cell line. Cells were co-transfected by electroporation with a transposase expression construct (pcDNA3.1-hy-mPB), a construct carrying the transposable full-length huCLDN18.1 (pPB-Puro-huCldn18.1) or huCLDN18.2 (pPB-Puro-huCldn18.2) and a puromycin expression cassette, and an EGFP-carrying construct (pEGFP-N3) as a transfection control. After transfection, cells were allowed to recover in growth medium in a humidified incubator at 37°C in a 5% CO2 atmosphere for two days. Transfection was verified by FC analysis of EGFP expression. Cells expressing huCLDN18.1 or huCLDN18.2 were then selected by adding puromycin to the culture at 1 μg / ml and further expanded to allow the generation of frozen stocks in FCS with 10% DMSO. The expression of huCLDN18.2 in transfected HEK293T cells was analyzed by FACS. Briefly, HEK293T cells were trypsinized and collected by centrifugation, resuspended in PBS / 2% FCS, and stained for huCLDN18.2 on ice for 30 min using IMAB362 as the primary antibody at 2 μg / ml, and after washing in PBS / 2% FCS, stained on ice for 30 min using PE-labeled anti-human FCγ-specific IgG goat antibody (eBioscience) as the secondary antibody. After further washing, the expression of huCLDN18.2 in transfected HEK293T cells was analyzed by FACS. Briefly, HEK293T cells were trypsinized and collected by centrifugation, resuspended in PBS / 2% FCS, and stained for huCLDN18.2 on ice for 30 min using IMAB362 as the primary antibody at 2 μg / ml, and after washing in PBS / 2% FCS, stained on ice for 30 min using PE-labeled anti-human FCγ-specific IgG goat antibody (eBioscience). TMInstrumental analysis of stained cells resuspended in ice-cold FACS buffer (see Figure 1A ). Untransfected parental cells that do not express CLDN18.2 were used as negative controls. In a similar manner, the expression of CLDN18.1 was analyzed using a proprietary pan-CLDN18 antibody that recognizes CLDN18.1 and CLDN18.2. Any pan-CLDN18 antibody that can be used for flow cytometry measurements is sufficient, such as anti-clauin-18 / CLDN18 (C-term) (Cat. No. AP50944PU-N) provided by OriGene Technologies, CLDN18 (C-term) rabbit pAb from MyBioSource (Cat. No. MBS8555451), or CLDN18 antibody from ProSci (Cat. No. 63-847).

[0125] Results: HEK293T cells stably expressing huCLDN18.1 and huCLDN18.2 were used to test the binding specificity of humanized antibodies hGBA-1, hGBA-2, hGBA-3, hGBA-4, hGBA-5, hGBA-6, hGBA-7, hGBA-8, and hGBA-9 to CLDN18.2, but not to CLDN18.1. Cells were stained with 2 μg / ml of antibody on ice for 30 minutes, washed in FACS buffer (PBS / 2% FCS), and then stained with a PE-conjugated anti-human Fcγ-specific IgG goat antibody (eBioscience) as a secondary antibody on ice for 30 minutes. The expression of CLDN18.1 in HEK293T cells stably expressing huCLDN18.1 was verified using a pan-CLDN18 antibody (see Figure 1, panel L), and the expression of CLDN18.2 in HEK293T cells stably expressing huCLDN18.2 was verified using IMAB362 (see Figure 1, panel A). Figure 1 shows that all humanized antibodies specifically bind to huCLDN18.2 expressed by HEK293T cells and do not specifically bind to huCLDN18.1. In addition, all humanized antibodies bind more strongly to huCLDN18.2 than the parent antibody IMAB362.

[0126] Example 3: ELISA binding analysis of humanized mAbs

[0127] The binding affinity of a humanized antibody (hGBA) to CLDN18.2 was tested in an ELISA assay using lipid particles carrying CLDN18.2 as the antigen source. CLDN18.2-lipid particles and empty lipid particles (no antigen as a negative control) were coated on 96-well plates at a final concentration of 10 U / ml. After washing with PBS / 0.05% Tween-20 (PBS-T) and blocking with PBS-T / 3% BSA for at least 1 hour at 37°C, 1:3 serial dilutions of hGBA and IMAB362 antibodies in PBS-T / 1% BSA were added to the coated wells at a starting concentration of 2 μg / ml and incubated at 37°C for at least 1 hour. The presence of bound antibody was revealed by binding of an HRP-based goat anti-human secondary antibody diluted in PBS-T / 1% BSA, developed using Sigma-Fast OPD as a peroxidase substrate, and stopped by adding 2 M H2SO4. The OD at 490 nm was then read on an ELISA plate reader. Representative binding curves are shown in Figure 2. Surprisingly, the binding curves in Figure 2 show that all humanized antibodies (hGBA-1 to hGBA-9) bind to CLDN18.2-lipid particles with higher affinities than IMAB362, as shown by higher maximum binding values.

[0128] Example 4: FC titration on HEK293T and PA-TU-8988 high cells

[0129] PA-TU-8988S cells expressing high levels of CLDN18.2 were selected by FACS (Creative Bioarray, catalog number CSC-C0326). Herein, these cells are designated as PA-TU-8988S-high cells. Based on FACS staining with IMAB362, PA-TU-8988S cell populations expressed different levels of CLDN18.2, with high expression and medium expression levels (see Figure 3A ). To obtain a more homogeneous cell population, cells were sorted by FACS, and only cells with high CLDN18.2 expression were selected. Briefly, PA-TU-8988S cells suspended in FACS buffer (PBS, 2% FCS) were incubated on ice for 30 min with 2 μg / mL of IMAB362. After washing in FACS buffer, cells were incubated on ice for 30 min with PE-labeled Fcγ-specific IgG goat anti-human secondary antibody (eBioscience). After washing, the stained cells were resuspended in FACS buffer and stained with a FACSAria TM The instrument was used for analysis and sorting, and the expressing cells ( Figure 3B ) and high-expressing cells ( Figure 3BAfter sorting, the collected PA-TU-8988S-high cells were resuspended in growth medium, expanded in growth medium, and frozen aliquots were stored in liquid N2.

[0130] To quantify the affinity of antibodies for CLDN18.2, HEK293T cells or PA-TU-8988-high cells overexpressing CLDN18.2 were cultured at 250 × 10 3 Cells / well were seeded in FC buffer (PBS / 2% FCS) in a 96-well plate and pelleted by centrifugation. The IMAB362 and hGBA antibodies to be tested were diluted at 4 μg / ml and then serially diluted 1:4 and incubated with the plated cells at 4°C for 30 minutes. After washing with FACS buffer, PE-conjugated anti-human IgG secondary antibody was added to the cells and continued at 4°C for an additional 30 minutes, followed by further washing with FC buffer. The cells were then resuspended in 100 μl FC buffer and stained with a FACSCalibur TM Cell analyzer (BD Biosciencies, USA) was used for measurement. FC analysis (see Figure 4 and Table 4) showed that all hGBA antibodies had stronger binding affinity for CLDN18.2 than IMAB362 in both cell lines (reflected in higher Max MFIs for all tested novel antibodies, see Table 4). The binding affinities of all hGBA antibodies were similar to each other but significantly higher than that of the parental antibody, IMAB362.

[0131] Table 4: All hGBAs on HEK293T cell line overexpressing CLDN18.2 and PA-TU-8988S-high cell line The maximum MFI and EC50 (μg / ml) were measured on the IgG and IMAB362 antibodies.

[0132]

[0133] The present invention is also described by the following embodiments:

[0134] 1. An antibody or fragment thereof that binds to CLDN18.2, comprising:

[0135] The HCDR1, HCDR2 and HCR3 sequences are SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the LCDR1, LCDR2 and LCDR3 sequences are SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

[0136] 2. The antibody or fragment thereof according to embodiment 1, comprising:

[0137] a. HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 18, respectively, and LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5, and SEQ ID NO: 29, respectively;

[0138] b. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 19, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0139] c. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 20, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 30, respectively;

[0140] d. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 12 and SEQ ID NO: 21, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 26, SEQ ID NO: 5 and SEQ ID NO: 30, respectively;

[0141] e. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 13 and SEQ ID NO: 18, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 31, respectively;

[0142] f. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 14 and SEQ ID NO: 22, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0143] g. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 15 and SEQ ID NO: 23, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 27, SEQ ID NO: 5 and SEQ ID NO: 29, respectively;

[0144] h. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 16 and SEQ ID NO: 23, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; or

[0145] i. The HCDR1, HCDR2 and HCDR3 sequences are SEQ ID NO: 8, SEQ ID NO: 17 and SEQ ID NO: 24, respectively, and the LCDR1, LCDR2 and LCDR3 sequences are SEQ ID NO: 28, SEQ ID NO: 5 and SEQ ID NO: 31, respectively.

[0146] 3. The antibody or fragment thereof according to embodiments 1 and 2, comprising:

[0147] a. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 32;

[0148] b. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 34;

[0149] c. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 35;

[0150] d. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 37;

[0151] e. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 39;

[0152] f. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 41;

[0153] g. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 42;

[0154] h. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 44, or

[0155] i. a VH sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 45;

[0156] as well as

[0157] j. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 33;

[0158] k. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 36;

[0159] 1. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 38;

[0160] m. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40;

[0161] n. a VL sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 43; or

[0162] o. A VL sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 46.

[0163] 4. The antibody or fragment thereof according to any one of embodiments 1 to 3, comprising:

[0164] a. VH sequence of SEQ ID NO: 32;

[0165] b. VH sequence of SEQ ID NO: 34;

[0166] c. VH sequence of SEQ ID NO: 35;

[0167] d. VH sequence of SEQ ID NO: 37;

[0168] e. VH sequence of SEQ ID NO: 39;

[0169] f. VH sequence of SEQ ID NO: 41;

[0170] g. VH sequence of SEQ ID NO: 42;

[0171] h. the VH sequence of SEQ ID NO: 44; or

[0172] i. VH sequence of SEQ ID NO: 45;

[0173] as well as

[0174] j. VL sequence of SEQ ID NO: 33;

[0175] k. VL sequence of SEQ ID NO: 36;

[0176] 1. VL sequence of SEQ ID NO: 38;

[0177] m. VL sequence of SEQ ID NO: 40;

[0178] n. the VL sequence of SEQ ID NO: 43; or

[0179] o. VL sequence of SEQ ID NO:46.

[0180] 5. The antibody or fragment thereof according to any one of embodiments 1 to 4, comprising:

[0181] a. VH sequence of SEQ ID NO: 32 and VL sequence of SEQ ID NO: 33;

[0182] b. VH sequence of SEQ ID NO: 34 and VL sequence of SEQ ID NO: 33;

[0183] c. VH sequence of SEQ ID NO: 35 and VL sequence of SEQ ID NO: 36;

[0184] d. VH sequence of SEQ ID NO: 37 and VL sequence of SEQ ID NO: 38;

[0185] e. VH sequence of SEQ ID NO: 39 and VL sequence of SEQ ID NO: 40;

[0186] f. VH sequence of SEQ ID NO:41 and VL sequence of SEQ ID NO:33;

[0187] g. VH sequence of SEQ ID NO: 42 and VL sequence of SEQ ID NO: 43;

[0188] h. the VH sequence of SEQ ID NO: 44 and the VL sequence of SEQ ID NO: 33; or

[0189] i. VH sequence of SEQ ID NO:45 and VL sequence of SEQ ID NO:46.

[0190] 6. The antibody or fragment thereof according to any one of embodiments 1 to 5, consisting of:

[0191] a. a heavy chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 49, and a light chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50;

[0192] b. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 51, and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50;

[0193] c. a heavy chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, and a light chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53;

[0194] d. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55;

[0195] e. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 57;

[0196] f. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50;

[0197] g. a heavy chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 59, and a light chain sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60;

[0198] h. a heavy chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 61, and a light chain sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50; or

[0199] i. a heavy chain sequence that has at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 62, and a light chain sequence that has at least 80%, at least 85%, at least 90%, at least 95% or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63.

[0200] 7. The antibody or fragment thereof according to any one of embodiments 1 to 6, consisting of:

[0201] a. the heavy chain sequence of SEQ ID NO: 49 and the light chain sequence of SEQ ID NO: 50;

[0202] b. the heavy chain sequence of SEQ ID NO: 51 and the light chain sequence of SEQ ID NO: 50;

[0203] c. the heavy chain sequence of SEQ ID NO: 52 and the light chain sequence of SEQ ID NO: 53;

[0204] d. the heavy chain sequence of SEQ ID NO: 54 and the light chain sequence of SEQ ID NO: 55;

[0205] e. the heavy chain sequence of SEQ ID NO: 56 and the light chain sequence of SEQ ID NO: 57;

[0206] f. the heavy chain sequence of SEQ ID NO: 58 and the light chain sequence of SEQ ID NO: 50;

[0207] g. the heavy chain sequence of SEQ ID NO: 59 and the light chain sequence of SEQ ID NO: 60;

[0208] h. the heavy chain sequence of SEQ ID NO: 61 and the light chain sequence of SEQ ID NO: 50; or

[0209] i. The heavy chain sequence of SEQ ID NO: 62 and the light chain sequence of SEQ ID NO: 63.

[0210] 8. An antibody or fragment thereof that competes for binding with the antibody or fragment thereof according to any one of embodiments 1 to 7.

[0211] 9. The antibody or fragment thereof according to any one of embodiments 1 to 8, wherein the form of the antibody or fragment thereof is selected from the group consisting of: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, synthetic IgG, IgM, F(ab)2, Fv, scFv, IgGACH2, F(ab')2, scFvCH3, Fab, VL, VH, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, non-depleted IgG, diabodies and bivalent antibodies, or Fc-engineered versions thereof.

[0212] 10. The antibody or fragment thereof according to any one of embodiments 1 to 9, wherein the antibody or fragment thereof is humanized.

[0213] 11. The antibody or fragment thereof according to any one of embodiments 1 to 10, wherein the antibody or fragment thereof is isolated.

[0214] 12. The antibody or fragment thereof according to any one of embodiments 1 to 11, wherein the antibody or fragment thereof does not bind to CLDN18.1.

[0215] 13. The antibody or fragment thereof according to any one of embodiments 1 to 12, wherein the antibody or fragment thereof shows enhanced binding to CLDN18.2 compared to antibody IMAB362.

[0216] 14. The antibody or fragment according to embodiment 13, wherein the enhanced binding is measured as an EC50 value and / or a maxMFI value by flow cytometry titration on cells expressing CLDN18.2, preferably wherein the cells are HEK293T cells or PA-TU-8988-high cells.

[0217] 15. The antibody or fragment according to embodiment 14, wherein the measured EC50 value of the antibody is at least 10% lower, at least 20% lower, at least 40% lower, at least 50% lower or at least 75% lower than the EC50 value of antibody IMAB362.

[0218] 16. The antibody or fragment according to embodiment 14, wherein the measured maxMFI value of the antibody is at least 10% higher, at least 20% higher, at least 40% higher, at least 50% higher or at least 75% higher than the maxMFI value of antibody IMAB362.

[0219] 17. A nucleic acid encoding the antibody or fragment thereof according to any one of embodiments 1 to 16.

[0220] 18. A vector comprising the nucleic acid of embodiment 17.

[0221] 19. A host cell comprising the nucleic acid of embodiment 17 or the vector of embodiment 18.

[0222] 20. The antibody or fragment thereof according to any one of embodiments 1 to 16, the nucleic acid according to embodiment 17, the vector according to embodiment 18 or the host cell according to embodiment 19, for use in treating a subject:

[0223] a. Suffering from neoplastic diseases,

[0224] b. are at risk of developing a neoplastic disease, and / or

[0225] c. Diagnosed with a neoplastic disease.

[0226] 21. The antibody or fragment thereof for use according to embodiment 20, wherein the neoplastic disease is selected from the group consisting of pancreatic cancer, gastric cancer, esophageal cancer, ovarian cancer and lung cancer.

[0227] sequence

[0228] SEQ ID NO: 1 GYXFTSYWIG X at position 3 is T or S

[0229] SEQ ID NO: 2 GXIYPXXXXTXYX: X at position 2 is N or I; X at position 6 is S or G; X at position 7 is A, E or D; X at position 8 is A or S; X at position 9 is Y or D; X at position 11 is N or R; X at the last position is A or S

[0230] SEQ ID NO:3 XRXWRGNSFDX: X at position 1 is A or T; X at position 3 is L, M, I or Q; X at position 4 is A or Y

[0231] SEQ ID NO:4 KSSQSXLNSGNQKNYLX The sixth X is L or V; the last X is T or A

[0232] SEQ ID NO:5 WASTRES

[0233] SEQ ID NO:6 QXDYSYPXT The second X is N or Q; X in L or F

[0234] SEQ ID NO:7 GYSFTSYWIG

[0235] SEQ ID NO:8 GYTFTSYWIG

[0236] SEQ ID NO:9 GNIYPGASDTRYA

[0237] SEQ ID NO:10 GNIYPGDADTRYA

[0238] SEQ ID NO:11 GIIYPGASDTNYA

[0239] SEQ ID NO:12 GIIYPGDAYTRYS

[0240] SEQ ID NO:13 GIIYPGAAYTRYA

[0241] SEQ ID NO:14 GNIYPGASYTRYS

[0242] SEQ ID NO:15 GNIYPGEAYTRYS

[0243] SEQ ID NO:16 GNIYPSESYTNYA

[0244] SEQ ID NO:17 GIIYPSAAYTRYA

[0245] SEQ ID NO:18 ARLWRGNSFDY

[0246] SEQ ID NO:19 ARMWRGNSFDY

[0247] SEQ ID NO:20 ARIWRGNSFDY

[0248] SEQ ID NO:21 TRLWRGNSFDA

[0249] SEQ ID NO:22 TRQWRGNSFDY

[0250] SEQ ID NO:23 TRLWRGNSFDY

[0251] SEQ ID NO:24 TRMWRGNSFDY

[0252] SEQ ID NO:25 KSSQSLLNSGNQKNYLA

[0253] SEQ ID NO:26 KSSQSLLNSGNQKNYLT

[0254] SEQ ID NO:27 KSSQSVLNSGNQKNYLT

[0255] SEQ ID NO:28 KSSQSVLNSGNQKNYLA

[0256] SEQ ID NO:29 QNDYSYPFT

[0257] SEQ ID NO:30 QNDYSYPLT

[0258] SEQ ID NO:31 QQDYSYPFT

[0259] SEQ ID NO:32 hGBA-1HC variable region

[0260] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARLWRGNSFDYWGQGTLVTVSS

[0261] SEQ ID NO:33 hGBA-1, hGBA-2, hGBA-6, hGBA-8LC variable region

[0262] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFGQGTKVEIK

[0263] SEQ ID NO:34 hGBA-2HC variable region

[0264] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGDADTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMWRGNSFDYWGQGTLVTVSS

[0265] SEQ ID NO:35 hGBA-3HC variable region

[0266] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARIWRGNSFDYWGQGTLVTVSS

[0267] SEQ ID NO:36 hGBA-3LC variable region

[0268] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKVEIK

[0269] SEQ ID NO:37 hGBA-4HC variable region

[0270] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDAWGQGTLVTVSS

[0271] SEQ ID NO:38 hGBA-4LC variable region

[0272] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKVEIK

[0273] SEQ ID NO:39 hGBA-5HC variable region

[0274] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARLWRGNSFDYWGQGTLVTVSS

[0275] SEQ ID NO:40 hGBA-5LC variable region

[0276] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQDYSYPFTFGQGTKVEIK

[0277] SEQ ID NO:41 hGBA-6HC variable region

[0278] EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGNIYPGASYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRQWRGNSFDYWGQGTLVTVSS

[0279] SEQ ID NO:42 hGBA-7HC variable region

[0280] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGEAYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDYWGQGTLVTVSS

[0281] SEQ ID NO:43 hGBA-7LC variable region

[0282] DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFGQGTKVEIK

[0283] SEQ ID NO:44 hGBA-8HC variable region

[0284] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDYWGQGTLVTVSS

[0285] SEQ ID NO:45 hGBA-9HC variable region

[0286] EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRMWRGNSFDYWGQGTLVTVSS

[0287] SEQ ID NO:46 hGBA-9LC variable region

[0288] DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQDYSYPFTFGQGTKVEIK

[0289] SEQ ID NO:47 IMAB362 HC full

[0290] QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0291] SEQ ID NO:48 IMAB362 LC full

[0292] DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0293] SEQ ID NO:49 hGBA-1HC full

[0294] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGASDTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0295] SEQ ID NO:50 hGBA-1,hGBA-2,hGBA-6,hGBA-8LC full

[0296] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0297] SEQ ID NO:51 hGBA-2 HC full

[0298] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGDADTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARMWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0299] SEQ ID NO:52 hGBA-3 HC full

[0300] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGASDTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARIWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0301] SEQ ID NO:53 hGBA-3 LC full

[0302] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0303] SEQ ID NO:54 hGBA-4 HC full

[0304] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDAYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0305] SEQ ID NO:55 hGBA-4 LC full

[0306] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0307] SEQ ID NO:56 hGBA-5 HC full

[0308] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0309] SEQ ID NO:57 hGBA-5 LC full

[0310] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0311] SEQ ID NO:58 hGBA-6 HC full

[0312] EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGNIYPGASYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRQWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0313] SEQ ID NO:59 hGBA-7 HC full

[0314] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPGEAYTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0315] SEQ ID NO:60 hGBA-7 LC full

[0316] DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0317] SEQ ID NO:61 hGBA-8 HC full

[0318] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGNIYPSESYTNYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRLWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0319] SEQ ID NO:62 hGBA-9 HC full

[0320] EVQLVQSGAEVKKPGESLKISCKGSGYTFTSYWIGWVRQMPGKGLEWMGIIYPSAAYTRYAPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCTRMWRGNSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0321] SEQ ID NO:63 hGBA-9, LC full

[0322] DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQDYSYPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0323] SEQ ID NO:64 Constant heavy chain - CH1 + Fc domain

[0324] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0325] SEQ ID NO:65

[0326] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0327] SEQ ID NO:66

[0328] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0329] SEQ ID NO:67

[0330] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0331] SEQ ID NO:68 DQWSTQDLYN

[0332] SEQ ID NO:69 NNPVTAVFNYQ

[0333] SEQ ID NO:70 STQDLYNNPVTAVF

[0334] SEQ ID NO:71 TNFWMSTANMYTG

[0335] SEQ ID NO:72 ALMIVGIVLGAIGLLV

[0336] SEQ ID NO:73 RIGSMEDSAKANMTLTSGIMFIVS

[0337] SEQ ID NO:74

[0338] METDTLLLWVLLLWVPGSTGDAAQPARRARRTKLGTELGSTPVWWNSADGRMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRAAIQHSGGRSRRARTKTHLRRGSE

[0339] SEQ ID NO:75 MDQWSTQDLYNNPVT

[0340] SEQ ID NO:76 LYNNPVTAVFNYQGL

[0341] SEQ ID NO:77 VFNYQGLWRSCVRES

[0342] SEQ ID NO:78 QGLWRSCVRESSGFT

[0343] SEQ ID NO:79 RSCVRESSGFTECRG

[0344] SEQ ID NO:80 TEDEVQSYPSKHDYV

[0345] SEQ ID NO:81 EVQSYPSKHDYV

[0346] SEQ ID NO:82 consensus, including IMAB362 HC CDR1

[0347] GYXFTSYWIX The third X is T or S, and the last X is G or N

[0348] SEQ ID NO:83 consensus, including IMAB362 HC CDR2

[0349] GXIYPXXXXTXYX: X in the second position is N or I; X in the sixth position is S or G; X in the seventh position is A, E, or D; X in the eighth position is A or S; X in the ninth position is Y or D; X in the eleventh position is N or R; X in the last position is A, N, or S

[0350] SEQ ID NO:84 consensus, including IMAB362 HC CDR3

[0351] XRXWRGNSFDX: The first X is A or T; the third X is L, M, I, S, or Q; the last X is A or Y

[0352] SEQ ID NO:85 ggctatagctttacatcatattggattgga

[0353] SEQ ID NO:86gggaacatttaccctggggcatcggatacgcgatacgca

[0354] SEQ ID NO:87 gcgagactttggcgggggaatagcttcgactac

[0355] SEQ ID NO:88 aaaagctcccaaagcctattgaactcgggaaaccaaaagaattacttggca

[0356] SEQ ID NO:89 tgggcaagcacccgagagagc

[0357] SEQ ID NO:90 caaaacgactattcatacccattcaca

[0358] SEQ ID NO:91 ggatattcatttacaagctactggatcgga

[0359] SEQ ID NO:92 ggaaatatataccccggagacgcggacacgagatacgca

[0360] SEQ ID NO:93 gcgcggatgtggcgcggcaatagctttgactac

[0361] SEQ ID NO:94 gggatcatctatccgggggcatccgataccaactatgcg

[0362] SEQ ID NO:95 gctaggatttggcgaggaaatagctttgattat

[0363] SEQ ID NO:96 aagagctcgcaaagtttgctgaactccgggaaccaaaagaattacctggca

[0364] SEQ ID NO:97 tgggcatcaacgcgggaaagc

[0365] SEQ ID NO:98 caaaacgactactcctatccgctgacc

[0366] SEQ ID NO:99 ggatactcatttacatcatactggatagga

[0367] SEQ ID NO:100 gggattatataccccggcgacgcttacactcgatattcg

[0368] SEQ ID NO:101 acgaggctatggagggggaatagctttgatgcc

[0369] SEQ ID NO:102 aagagctcccaaagcctattgaactcgggaaatcaaaagaattatctgaca

[0370] SEQ ID NO:103 tgggcctcgacaagggagagc

[0371] SEQ ID NO:104 caaaatgactactcatacccgctgaca

[0372] SEQ ID NO:105 ggatatagctttacgagctactggatcgga

[0373] SEQ ID NO:106 gggataatataccccggagcggcatacacgagatatgcg

[0374] SEQ ID NO:107 gcgagactatggcgcgggaactcatttgattac

[0375] SEQ ID NO:108 aaatcatcgcaatcattgctaaattcggggaaccaaaagaattatttggca

[0376] SEQ ID NO:109 tgggcatccacgagagaatcg

[0377] SEQ ID NO:110 caacaagattattcatacccatttaca

[0378] SEQ ID NO:111 ggatatacatttacatcttactggatcgga

[0379] SEQ ID NO:112 gggaacatttatcctggcgcgagctatacgcgctat

[0380] SEQ ID NO:113 acccggcaatggaggggcaatagctttgactac

[0381] SEQ ID NO:114 ggatattcctttacatcatactggatcggc

[0382] SEQ ID NO:115 gggaacatatatcccggagaagcctatacgagatactcg

[0383] SEQ ID NO:116 acgcgactatggaggggaaatagctttgactat

[0384] SEQ ID NO:117 aagagctcccaatcagtcctgaactctgggaatcaaaagaattacctgaca

[0385] SEQ ID NO:118 tgggcgagcacgagggagagc

[0386] SEQ ID NO:119 caaaatgattattcataccccttcaca

[0387] SEQ ID NO:120 ggatactcctttacatcatattggatcgga

[0388] SEQ ID NO:121 ggaaacatatatccgagcgaatcatatacgaactacgcg

[0389] SEQ ID NO:122 acgaggctatggagggggaatagcttcgactat

[0390] SEQ ID NO:123 ggatatacattcacgagctactggatagga

[0391] SEQ ID NO:124 ggaatcatatatccttccgcggcatatacgcgatatgcg

[0392] SEQ ID NO:125 acgcggatgtggaggggaaatagctttgattac

[0393] SEQ ID NO:126 aagagctcgcaatcggtcctgaatagcgggaaccaaaagaattatctggcc

[0394] SEQ ID NO:127 caacaagactactcatacccatttaca

[0395] SEQ ID NO:128

[0396] gaagtccaactggtccaatccggcgcggaggttaagaagcccggagaatcgctgaagatctcatgcaaagggagcggctatagctttacatcatattggattggatgggtcaggcaaatgccggggaaggggctggaatggatggggaacatttaccctggggcatcggatacgcgatacgcacctagctttcaagggcaagtcacaatttcggcggacaagagcatctcaacggcatacctgcaatggtcgagcttgaaggcatctgatactgcaatgtactactgcgcgagactttggcgggggaatagcttcgactactgggggcagggtaccctggttacggtctcgagc

[0397] SEQ ID NO:129

[0398] gacattgtgatgacgcaaagccccgattcgctggctgtatcgctaggggagcgcgctacgatcaattgcaaaagctcccaaagcctattgaactcgggaaaccaaaagaattacttggcatggtatcaacaaaaaccggggcaaccgccgaagctgctgatctattgggcaagcacccgagagagcggtgtcccggaccgatttagcgggagcggatcgggcaccgacttcacgctgacaataagctcattgcaagccgaggatgtggcggtctattattgccaaaacgactattcatacccattcacattcgggcaaggtaccaaggtcgagatcaag

[0399] SEQ ID NO:130

[0400] gaagtccaactggtccaatctggagcggaagtcaagaagcctggggagagcctgaaaatttcatgcaaggggagcggatattcatttacaagctactggatcggatgggtccggcaaatgccggggaagggcttggaatggatgggaaatatataccccggagacgcggacacgagatacgcaccgagctttcaagggcaggtcaccattagcgctgataaatcgatttcaaccgcatatctgcaatggtcatcgctgaaggcctccgacaccgcgatgtactattgcgcgcggatgtggcgcggcaatagctttgactactgggggcagggtaccctcgtcacggtctcgagc

[0401] SEQ ID NO:131

[0402] gaggtccaactggtccaaagcggcgcggaggtcaagaagccgggagaatccctgaagattagctgcaaaggctccggctatagctttacatcatattggatcggatgggtcagacaaatgccgggaaagggacttgaatggatggggatcatctatccgggggcatccgataccaactatgcgccgagcttccaagggcaggtcacgatatccgcggataaatcgattagcaccgcatatctgcaatggagctcgctgaaggcatccgacaccgcgatgtactactgcgctaggatttggcgaggaaatagctttgattattgggggcagggtacccttgtcacggtctcgagc

[0403] SEQ ID NO:132

[0404] gacattgtcatgacgcaaagccccgactcgctggccgtctcactgggggagcgggcgacaatcaactgcaagagctcgcaaagtttgctgaactccgggaaccaaaagaattacctggcatggtatcaacaaaagccggggcaacccccgaagctgctgatatattgggcatcaacgcgggaaagcggagtcccggatagatttagcggatctggatcggggaccgacttcacgctgacgatatctagccttcaagccgaggatgtggctgtatattattgccaaaacgactactcctatccgctgaccttcgggcaaggtaccaaggtcgagatcaag

[0405] SEQ ID NO:133

[0406] gaagtccaactagtccaaagcggagccgaagtcaagaaaccgggggagagccttaagatctcatgcaaggggagcggatactcatttacatcatactggataggatgggtcagacaaatgcccggcaaggggctggaatggatggggattatataccccggcgacgcttacactcgatattcgccatcattccaagggcaggtcacgatatcggccgataaatcgatatccacggcatacctgcaatggagctcactgaaagcatctgatacggcaatgtattattgcacgaggctatggagggggaatagctttgatgcctgggggcagggtaccctggtcacggtctcgagc

[0407] SEQ ID NO:134

[0408] gacatagttatgacacaatcgccggatagcctcgcggtcagccttggagagcgggcgacgatcaactgcaagagctcccaaagcctattgaactcgggaaatcaaaagaattatctgacatggtatcaacaaaagccggggcaaccaccgaaactgctgatctattgggcctcgacaagggagagcggagtcccggaccgcttctctggatcgggaagcgggactgacttcacgctgaccataagctcgctgcaagccgaggacgtcgccgtctattattgccaaaatgactactcatacccgctgacatttggccaaggtaccaaggtcgagatcaag

[0409] SEQ ID NO:135

[0410] gaggtgcaactggtacaatccggggcggaagtgaagaagccgggggaatcgctgaagataagctgcaaaggctctggatatagctttacgagctactggatcggatgggtcaggcaaatgccggggaagggactggaatggatggggataatataccccggagcggcatacacgagatatgcgccgagcttccaagggcaagtgacaataagcgcggacaaatcgattagcacggcatatctgcaatggtcctcgctgaaggcgagcgataccgcaatgtactattgcgcgagactatggcgcgggaactcatttgattactgggggcagggtaccctagtgacggtctcgagc

[0411] SEQ ID NO:136

[0412] gacattgtcatgacgcaaagcccggatagcctggctgtatcgctgggggagagagcgacgatcaactgcaaatcatcgcaatcattgctaaattcggggaaccaaaagaattatttggcatggtatcaacaaaagccggggcaaccgccgaaactgctgatttactgggcatccacgagagaatcgggagtcccggaccgatttagcggatctgggagcgggaccgatttcacgctgaccattagctcgctgcaagcggaggatgtggcggtctattactgccaacaagattattcatacccatttacatttgggcaaggtaccaaggtcgagatcaag

[0413] SEQ ID NO:137

[0414] gaagtacaattggttcaatcgggggccgaagtcaagaagccgggggaatcgctgaagatatcctgcaaggggagcggatatacatttacatcttactggatcggatgggtcagacaaatgcccggaaaggggcttgaatggatggggaacatttatcctggcgcgagctatacgcgctatagcccgagcttccaagggcaggtcacgattagcgccgacaagagcatttcgacggcatacctgcaatggagctcgctgaaagcatcggatacggcaatgtattactgcacccggcaatggaggggcaatagctttgactactgggggcagggtaccctagtcacggtctcgagc

[0415] SEQ ID NO:138

[0416] gaagttcaattggtccaatctggagccgaagtcaagaagcccggagaatcgctgaagattagctgcaaggggagcggatattcctttacatcatactggatcggctgggtcagacaaatgcccggaaagggactggaatggatggggaacatatatcccggagaagcctatacgagatactcgccatcatttcaaggacaggtcaccataagcgcggacaagagcataagcaccgcatacctgcaatggagctcgctgaaggcatcggacaccgccatgtattactgcacgcgactatggaggggaaatagctttgactattgggggcagggtaccttagtcacggtctcgagc

[0417] SEQ ID NO:139

[0418] gatatagtaatgactcaatcacccgatagcttggctgtgagcctgggagaaagagctacaatcaactgcaagagctcccaatcagtcctgaactctgggaatcaaaagaattacctgacatggtatcaacaaaagcccggacaaccgccgaagctgctgatctactgggcgagcacgagggagagcggagtcccggatcgattttctggctccgggagcggaaccgacttcacactgactattagctcgctgcaagcggaggacgtcgccgtctactattgccaaaatgattattcataccccttcacatttgggcaaggtaccaaggtcgagatcaag

[0419] SEQ ID NO:140

[0420] gaggtgcaactagtgcaatcgggggccgaagtgaagaaacctggggaatcgctgaagatatcatgcaaggggagcggatactcctttacatcatattggatcggatgggtcaggcaaatgccggggaaggggctggaatggatgggaaacatatatccgagcgaatcatatacgaactacgcgccgagctttcaaggacaagtcacgatatccgcggataaatcgatatcgaccgcatacctgcaatggagctcgctgaaggcttccgacactgcgatgtattactgcacgaggctatggagggggaatagcttcgactattgggggcagggtaccctggtgacggtctcgagc

[0421] SEQ ID NO:141

[0422] gaagtccaattagtccaatcgggggccgaggtcaagaagccgggggaatcgctcaagataagctgcaagggatcgggatatacattcacgagctactggataggatgggtcaggcaaatgccggggaaggggctggaatggatgggaatcatatatccttccgcggcatatacgcgatatgcgccatcatttcaaggacaggtcacgataagcgccgacaagagcattagcaccgcatacctgcaatggtcgagccttaaggcatcggacaccgcgatgtactactgcacgcggatgtggaggggaaatagctttgattactgggggcagggtaccctagtcacggtctcgagc

[0423] SEQ ID NO:142

[0424] gacatcgtcatgacgcaaagcccggactcgctggcggtctcgctgggggagcgggccacaataaattgcaagagctcgcaatcggtcctgaatagcgggaaccaaaagaattatctggcctggtatcaacaaaagccggggcaaccaccgaagctgctaatctattgggcgagcacgagggagagcggagtccccgatcgatttagcggatcgggaagcgggaccgatttcacgctgacgatttcgagcctacaagccgaggatgtggcggtctattactgccaacaagactactcatacccatttacatttggacaaggtaccaaggtcgagatcaag

[0425] SEQ ID NO:143 Sortase tag

[0426] RLPXTGG

[0427] X is any one of the 20 natural amino acids

[0428] SEQ ID NO:144 Sortase tag

[0429] GGGGSLPXTGG

[0430] X is any one of the 20 natural amino acids

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[0471] CN109762067

[0472] WO2000 / 015659

[0473] WO2004 / 047863

[0474] WO2005 / 113587

[0475] WO2007 / 059997

[0476] WO2008 / 145338

[0477] WO2013 / 167259

[0478] WO2013 / 174509

[0479] WO2014 / 075788

[0480] WO2014 / 127906

[0481] WO2016 / 166122

[0482] WO2018 / 006882

[0483] WO2019 / 175617

[0484] WO2019 / 219089 Sequence Listing <110> Sidian Biotech <120> Humanized CLDN18.2 antibody <130> S12415WO / SOTCLD-1903WO <150> EP 19 214 104.2 <151> 2019-12-06 <160> 144 <170> PatentIn version 3.5 <210> 1 <211> 10 <212> PRT <213> Artificial sequence <220> <223> HCDR1 consensus sequence <220> <221> MISC_FEATURE <222> (3) <223> T or S <400> 1 Gly Tyr Xaa Phe Thr Ser Tyr Trp Ile Gly 1 5 10 <210> 2 <211> 13 <212> PRT <213> Artificial sequence <220> <223> HCDR2 consensus sequence <220> <221> MISC_FEATURE <222> (2)..(2) <223> N or I <220> <221> MISC_FEATURE <222> (6) <223> S or G <220> <221> MISC_FEATURE <222> (7)..(7) <223> A, E, or D <220> <221> MISC_FEATURE <222> (8)..(8) <223> A or S <220> <221> MISC_FEATURE <222> (9)..(9) <223> Y or D <220> <221> MISC_FEATURE <222> (11)..(11) <223> N or R <220> <221> MISC_FEATURE <222> (13) <223> A or S <400> 2 Gly Xaa Ile Tyr Pro Xaa Xaa Xaa Xaa Thr Xaa Tyr Xaa 1 5 10 <210> 3 <211> 11 <212> PRT <213> Artificial sequence <220> <223> HCDR3 consensus sequence <220> <221> MISC_FEATURE <222> (1)..(1) <223> A or T <220> <221> MISC_FEATURE <222> (3) <223> L, M, I, or Q <220> <221> MISC_FEATURE <222> (11)..(11) <223> A or Y <400> 3 Xaa Arg Xaa Trp Arg Gly Asn Ser Phe Asp Xaa 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial sequence <220> <223> LCDR1 consensus sequence <220> <221> MISC_FEATURE <222> (6) <223> L or V <220> <221> MISC_FEATURE <222> (17) <223> T or A <400> 4 Lys Ser Ser Gln Ser Xaa Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Xaa <210> 5 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR2 consensus sequence <400> 5 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR3 consensus sequence <220> <221> MISC_FEATURE <222> (2)..(2) <223> N or Q <220> <221> MISC_FEATURE <222> (8)..(8) <223> L or F <400> 6 Gln Xaa Asp Tyr Ser Tyr Pro Xaa Thr 1 5 <210> 7 <211> 10 <212> PRT <213> Artificial sequence <220> <223> hGBA-1, hGBA-2, hGBA-3, hGBA-4, hGBA-5, hGBA-7, hGBA-8 HCDR1 sequence <400> 7 Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly 1 5 10 <210> 8 <211> 10 <212> PRT <213> Artificial sequence <220> <223> hGBA-6, hGBA-9 HCDR1 sequences <400> 8 Gly Tyr Thr Phe Thr Ser Tyr Trp Ile Gly 1 5 10 <210> 9 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-1 HCDR2 sequence <400> 9 Gly Asn Ile Tyr Pro Gly Ala Ser Asp Thr Arg Tyr Ala 1 5 10 <210> 10 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-2 HCDR2 sequence <400> 10 Gly Asn Ile Tyr Pro Gly Asp Ala Asp Thr Arg Tyr Ala 1 5 10 <210> 11 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-3 HCDR2 sequence <400> 11 Gly Ile Ile Tyr Pro Gly Ala Ser Asp Thr Asn Tyr Ala 1 5 10 <210> 12 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-4 HCDR2 sequence <400> 12 Gly Ile Ile Tyr Pro Gly Asp Ala Tyr Thr Arg Tyr Ser 1 5 10 <210> 13 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-5 HCDR2 sequence <400> 13 Gly Ile Ile Tyr Pro Gly Ala Ala Tyr Thr Arg Tyr Ala 1 5 10 <210> 14 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-6 HCDR2 sequence <400> 14 Gly Asn Ile Tyr Pro Gly Ala Ser Tyr Thr Arg Tyr Ser 1 5 10 <210> 15 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-7 HCDR2 sequence <400> 15 Gly Asn Ile Tyr Pro Gly Glu Ala Tyr Thr Arg Tyr Ser 1 5 10 <210> 16 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-8 HCDR1 sequence <400> 16 Gly Asn Ile Tyr Pro Ser Glu Ser Tyr Thr Asn Tyr Ala 1 5 10 <210> 17 <211> 13 <212> PRT <213> Artificial sequence <220> <223> hGBA-9 HCDR2 sequence <400> 17 Gly Ile Ile Tyr Pro Ser Ala Ala Tyr Thr Arg Tyr Ala 1 5 10 <210> 18 <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-1, hGBA-5 HCDR3 sequences <400> 18 Ala Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> 19 <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-2 HCDR3 sequence <400> 19 Ala Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> 20 <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-3 HCDR3 sequence <400> 20 Ala Arg Ile Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> twenty one <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-4 HCDR3 sequence <400> twenty one Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Ala 1 5 10 <210> twenty two <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-6 HCDR3 sequence <400> twenty two Thr Arg Gln Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> twenty three <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-7, hGBA-8 HCDR3 sequences <400> twenty three Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> twenty four <211> 11 <212> PRT <213> Artificial sequence <220> <223> hGBA-9 HCDR3 sequence <400> twenty four Thr Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr 1 5 10 <210> 25 <211> 17 <212> PRT <213> Artificial sequence <220> <223> hGBA-1, hGBA-3, hGBA-5, hGBA-6, hGBA-8 LCDR1 sequence <400> 25 Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <210> 26 <211> 17 <212> PRT <213> Artificial sequence <220> <223> hGBA-4 LCDR1 sequence <400> 26 Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Thr <210> 27 <211> 17 <212> PRT <213> Artificial sequence <220> <223> hGBA-7 LCDR1 sequence <400> 27 Lys Ser Ser Gln Ser Val Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Thr <210> 28 <211> 17 <212> PRT <213> Artificial sequence <220> <223> hGBA-9 LCDR1 sequence <400> 28 Lys Ser Ser Gln Ser Val Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <210> 29 <211> 9 <212> PRT <213> Artificial sequence <220> <223> hGBA-1, hGBA-3, hGBA-6, hGBA-7, hGBA-8 LCDR3 sequence <400> 29 Gln Asn Asp Tyr Ser Tyr Pro Phe Thr 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial sequence <220> <223> hGBA-4 LCDR3 sequence <400> 30 Gln Asn Asp Tyr Ser Tyr Pro Leu Thr 1 5 <210> 31 <211> 9 <212> PRT <213> artificial sequence <220> <223> hGBA-5, hGBA-9 LCDR3 sequence <400> 31 Gln Gln Asp Tyr Ser Tyr Pro Phe Thr 1 5 <210> 32 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-1 VH sequence <400> 32 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Ala Ser Asp Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 33 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-1, hGBA-2, hGBA-6 , hGBA-8 VL sequence <400> 33 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Light <210> 34 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-2 VH sequence <400> 34 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Asp Ala Asp Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 35 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-3 VH sequence <400> 35 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Ala Ser Asp Thr Asn Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Ile Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 36 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-3 VL sequence <400> 36 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Light <210> 37 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-4 VH sequence <400> 37 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ala Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Ala Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 38 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-4 VL sequence <400> 38 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Light <210> 39 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-5 VH sequence <400> 39 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Ala Ala Tyr Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 40 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-5 VL sequence <400> 40 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Light <210> 41 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-6 VH sequence <400> 41 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Ala Ser Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Gln Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 42 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-7 VH sequence <400> 42 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Glu Ala Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 43 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-7 VL sequence <400> 43 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Light <210> 44 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-8 VH sequence <400> 44 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Ser Glu Ser Tyr Thr Asn Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 45 <211> 118 <212> PRT <213> artificial sequence <220> <223> hGBA-9 VH sequence <400> 45 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Ser Ala Ala Tyr Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 46 <211> 113 <212> PRT <213> artificial sequence <220> <223> hGBA-9 VL sequence <400> 46 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys <210> 47 <211> 448 <212> PRT <213> Artificial sequence <220> <223> IMAB362 HC full <400> 47 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 48 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Full-length IMAB362 Light Chain <400> 48 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 49 <211> 448 <212> PRT <213> artificial sequence <220> <223> hGBA-1 <400> 49 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Ala Ser Asp Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 50 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Light chain sequences of hGBA-1, hGBA-2, hGBA-6, hGBA-8 <400> 50 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 51 <211> 448 <212> PRT <213> artificial sequence <220> <223> hGBA-2 heavy chain sequence <400> 51 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Asp Ala Asp Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 52 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> hGBA-3 heavy chain sequence <400> 52 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Ala Ser Asp Thr Asn Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Ile Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 53 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> hGBA-3 short chain sequence <400> 53 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 54 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> hGBA-4 Heavy Chain Sequence <400> 54 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ala Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Ala Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 55 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> hGBA-4 Light Chain Sequence <400> 55 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 56 <211> 448 <212> PRT <213> Artificial sequence <220> <223> hGBA-5 heavy chain sequence <400> 56 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Ala Ala Tyr Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 57 <211> 220 <212> PRT <213> Artificial sequence <220> <223> hGBA-5 light chain sequence <400> 57 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 58 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> hGBA-6 Heavy Chain Sequence <400> 58 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Ala Ser Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Gln Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 59 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> hGBA-7 Heavy Chain Sequence <400> 59 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Gly Glu Ala Tyr Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 60 <211> 220 <212> PRT <213> artificial sequence <220> <223> hGBA-7 <400> 60 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 61 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> hGBA-8 Heavy Chain Sequence <400> 61 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 1*0 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Asn Ile Tyr Pro Ser Glu Ser Tyr Thr Asn Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Leu Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 62 <211> 448 <212> PRT <213> Artificial sequence <220> <223> hGBA-9 heavy chain sequence <400> 62 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 4s Gly Ile Ile Tyr Pro Ser Ala Ala Tyr Thr Arg Tyr Ala Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 It should be noted that there seems to be a typo in the original "4s" in line 37 which is likely a "45". This has been left as-is in the translation for the sake of following the instructions precisely.Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Met Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 63 <211> 220 <212> PRT <213> Artificial sequence <220> <223> hGBA-9 light chain sequence <400> 63 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 64 <211> 330 <212> PRT <213> artificial sequence <220> <223> Constant heavy chain - CH1 + Fc domain <400> 64 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 13​Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 65 <211> 107 <212> PRT <213> Synthetic sequence <220> <223> Constant light chain region <400> 65 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser ​​​​​​<210> 66 <211> 330 <212> PRT <213> Artificial sequence <220> <223> constant heavy chain region CH1 and Fc region, which have L234A / L235A mutations, Has reduced FcγR binding <400> 66 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 67 <211> 330 <212> PRT <213> Artificial sequence <220> <223> The constant heavy chain region CH1 and Fc region have L234A / L235A / P329G mutations, with even further reduced FcγR binding <400> 67 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 68 <211> 10 <212> PRT <213> Artificial sequence <220> <223> The N-terminal extracellular domain of CLDN18.2 is independent of glycosylation <400> 68 Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn 1 5 10 <210> 69 <211> 11 <212> PRT <213> Artificial sequence <220> <223> The N-terminal extracellular domain of CLDN18.2 is mainly unglycosylated <400> 69 Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln 1 5 10 <210> 70 <211> 14 <212> PRT <213> Artificial sequence <220> <223> N-terminal extracellular domain of CLDN18.2, unglycosylated <400> 70 Ser Thr Gln Asp Leu Tyr Asn Asn Pro Val Thr Ala Val Phe 1 5 10 <210> 71 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Pan-CLDN18 peptide <400> 71 Thr Asn Phe Trp Met Ser Thr Ala Asn Met Tyr Thr Gly 1 5 10 <210> 72 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Peptide sequences targeting specific epitopes on CLDN18.2 disclosed in WO2005 / 113587 <400> 72 Ala Leu Met Ile Val Gly Ile Val Leu Gly Ala Ile Gly Leu Leu Val 1 5 10 15 <210> 73 <211> twenty four <212> PRT <213> Artificial sequence <220> <223> Peptide sequences targeting specific epitopes on CLDN18.2 disclosed in WO2005 / 113587 <400> 73 Arg Ile Gly Ser Met Glu Asp Ser Ala Lys Ala Asn Met Thr Leu Thr 1 5 10 15 Ser Gly Ile Met Phe Ile Val Ser 20 <210> 74 <211> 129 <212> PRT <213> Artificial sequence <220> <223> Peptide comprising the first extracellular domain of CLDN18.2 with N-terminal and C-terminal extensions <400> 74 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ala Ala Gln Pro Ala Arg Arg Ala Arg Arg Thr 20 25 30 Lys Leu Gly Thr Glu Leu Gly Ser Thr Pro Val Trp Trp Asn Ser Ala 35 40 45 Asp Gly Arg Met Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn Asn Pro 50 55 60 Val Thr Ala Val Phe Asn Tyr Gln Gly Leu Trp Arg Ser Cys Val Arg 65 70 75 80 Glu Ser Ser Gly Phe Thr Glu Cys Arg Gly Tyr Phe Thr Leu Leu Gly 85 90 95 Leu Pro Ala Met Leu Gln Ala Val Arg Ala Ala Ile Gln His Ser Gly 100 105 110 Gly Arg Ser Arg Arg Ala Arg Thr Lys Thr His Leu Arg Arg Gly Ser 115 120 125 Glu <210> 75 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Overlapping peptides within the first extracellular domain of CLDN18.2 <400> 75 Met Asp Gln Trp Ser Thr Gln Asp Leu Tyr Asn Asn Pro Val Thr 1 5 10 15 <210> 76 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Overlapping peptides within the first extracellular domain of CLDN18.2 <400> 76 Leu Tyr Asn Asn Pro Val Thr Ala Val Phe Asn Tyr Gln Gly Leu 1 5 10 15 <210> 77 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Overlapping peptides within the first extracellular domain of CLDN18.2 <400> 77 Val Phe Asn Tyr Gln Gly Leu Trp Arg Ser Cys Val Arg Glu Ser 1 5 10 15 <210> 78 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Overlapping peptides within the first extracellular domain of CLDN18.2 <400> 78 Gln Gly Leu Trp Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr 1 5 10 15 <210> 79 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Overlapping peptides within the first extracellular domain of CLDN18.2 <400> 79 Arg Ser Cys Val Arg Glu Ser Ser Gly Phe Thr Glu Cys Arg Gly 1 5 10 15 <210> 80 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Epitope of the antibody of WO2013 / 167259 that binds to the C-terminal epitope of CLDN18.2 <400> 80 Thr Glu Asp Glu Val Gln Ser Tyr Pro Ser Lys His Asp Tyr Val 1 5 10 15 <210> 81 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Epitope of the antibody of WO2013 / 167259 that binds to the C-terminal epitope of CLDN18.2 <400> 81 Glu Val Gln Ser Tyr Pro Ser Lys His Asp Tyr Val 1 5 10 <210> 82 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Shared, including IMAB362 HC CDR1 <220> <221> MISC_FEATURE <222> (3) <223> T or S <220> <221> MISC_FEATURE <222> (10)..(10) <223> G or N <400> 82 Gly Tyr Xaa Phe Thr Ser Tyr Trp Ile Xaa 1 5 10 <210> 83 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Shared, including IMAB362 HC CDR2 <220> <221> MISC_FEATURE <222> (2)..(2) <223> N or I <220> <221> MISC_FEATURE <222> (6) <223> S or G <220> <221> MISC_FEATURE <222> (7)..(7) <223> A, E, or D <220> <221> MISC_FEATURE <222> (8)..(8) <223> A or S <220> <221> MISC_FEATURE <222> (9)..(9) <223> Y or D <220> <221> MISC_FEATURE <222> (11)..(11) <223> N or R <220> <221> MISC_FEATURE <222> (13)..(13) <223> A, N or S <400> 83 Gly Xaa Ile Tyr Pro Xaa Xaa Xaa Xaa Thr Xaa Tyr Xaa 1 5 10 <210> 84 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Shared, including IMAB362 HC CDR3 <220> <221> MISC_FEATURE <222> (1)..(1) <223> A or T <220> <221> MISC_FEATURE <222> (3) <223> L, M, I, S or Q <220> <221> MISC_FEATURE <222> (11)..(11) <223> A or Y <400> 84 Xaa Arg Xaa Trp Arg Gly Asn Ser Phe Asp Xaa 1 5 10 <210> 85 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-1, hGBA-3 HCDR1 sequences <400> 85 ggctatagct ttacatcata ttggattgga 30 <210> 86 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-1 HCDR2 sequence <400> 86 gggaacattt accctggggc atcggatacg cgatacgca 39 <210> 87 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-1 HCDR3 sequence <400> 87 gcgagacttt ggcgggggaa tagcttcgac tac 33 <210> 88 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-1 LCDR1 sequence <400> 88 aaaagctccc aaagcctatt gaactcggga aaccaaaaga attacttggc a 51 <210> 89 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> hGBA-1 LCDR2 sequence <400> 89 tgggcaagca cccgagagag c 21 <210> 90 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-1 LCDR3 sequence <400> 90 caaaacgact attcataccc attcaca 27 <210> 91 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-2 HCDR1 sequence <400> 91 ggatattcat ttacaagcta ctggatcgga 30 <210> 92 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-2 HCDR2 sequence <400> 92 ggaaatat accccggaga cgcggacacg agatacgca 39 <210> 93 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-2 HCDR3 sequence <400> 93 gcgcggatgt ggcgcggcaa tagctttgac tac 33 <210> 94 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 HCDR2 sequence <400> 94 gggatcatct atccgggggc atccgatacc aactatgcg 39 <210> 95 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 HCDR3 sequence <400> 95 gctaggattt ggcgaggaaa tagctttgat tat 33 <210> 96 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 LCDR1 sequence <400> 96 aagagctcgc aaagtttgct gaactccggg aaccaaaaga attacctggc a 51 <210> 97 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> hGBA-3 LCDR2 sequence <400> 97 tgggcatcaa cgcgggaaag c 21 <210> 98 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 LCDR3 sequence <400> 98 caaaacgact actcctatcc gctgacc 27 <210> 99 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 HCDR1 sequence <400> 99 ggatactcat ttacatcata ctggatagga 30 <210> 100 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 HCDR2 sequence <400> 100 gggattatat accccggcga cgcttacact cgatattcg 39 <210> 101 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 HCDR3 sequence <400> 101 acgaggctat ggagggggaa tagctttgat gcc 33 <210> 102 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 LCDR1 sequence <400> 102 aagagctccc aaagcctatt gaactcggga aatcaaaaga attatctgac a 51 <210> 103 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> hGBA-4 LCDR2 sequence <400> 103 tgggcctcga caagggagag c 21 <210> 104 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 LCDR3 sequence <400> 104 caaaatgact actcataccc gctgaca 27 <210> 105 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 HCDR1 sequence <400> 105 ggatatagct ttacgagcta ctggatcgga 30 <210> 106 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 HCDR2 sequence <400> 106 gggataatat accccggagc ggcatacacg agatatgcg 39 <210> 107 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 HCDR3 sequence <400> 107 gcgagactat ggcgcgggaa ctcatttgat tac 33 <210> 108 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 LCDR1 sequence <400> 108 aaatcatcgc aatcattgct aaattcgggg aaccaaaaga attatttggc a 51 <210> 109 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> hGBA-5 LCDR2 sequence <400> 109 tgggcatcca cgagagaatc g 21 <210> 110 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 LCDR3 sequence <400> 110 caacaagatt attcataccc atttaca 27 <210> 111 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-6 HCDR1 sequence <400> 111 ggatatacat ttacatctta ctggatcgga 30 <210> 112 <211> 36 <212> DNA <213> Artificial sequence <220> <223> hGBA-6 HCDR2 sequence <400> 112 gggaacattt atcctggcgc gagctatacg cgctat 36 <210> 113 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-6 HCDR3 sequence <400> 113 acccggcaat ggaggggcaa tagctttgac tac 33 <210> 114 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-7 HCDR1 sequence <400> 114 ggatattcctttacatcatactggatcggc 30 <210> 115 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-7 HCDR2 sequence <400> 115 gggaacatat atcccggaga agcctatacg agatactcg 39 <210> 116 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-7 HCDR3 sequence <400> 116 acgcgactat ggaggggaaa tagctttgac tat 33 <210> 117 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-7 LCDR1 sequence <400> 117 aagagctccc aatcagtcct gaactctggg aatcaaaaga attacctgac a 51 <210> 118 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> hGBA-7, h-GBA 9 LCDR2 sequences <400> 118 tgggcgagca cgagggagag c 21 <210> 119 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-7 LCDR3 sequence <400> 119 caaaatgatt attcataccc cttcaca 27 <210> 120 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-8 HCDR1 sequence <400> 120 ggatactcctttacatcata ttggatcgga 30 <210> 121 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-8 HCDR2 sequence <400> 121 ggaaacatat atccgagcga atcatatacg aactacgcg 39 <210> 122 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-8 HCDR3 sequence <400> 122 acgaggctat ggagggggaa tagcttcgac tat 33 <210> 123 <211> 30 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 HCDR1 sequence <400> 123 ggatatacat tcacgagcta ctggatagga 30 <210> 124 <211> 39 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 HCDR2 sequence <400> 124 ggaatcatat atccttccgc ggcatatacg cgatatgcg 39 <210> 125 <211> 33 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 HCDR3 sequence <400> 125 acgcggatgt ggaggggaaa tagctttgat tac 33 <210> 126 <211> 51 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 LCDR1 sequence <400> 126 aagagctcgc aatcggtcct gaatagcggg aaccaaaaga attatctggc c 51 <210> 127 <211> 27 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 LCDR3 sequence <400> 127 caacaagact actcataccc atttaca 27 <210> 128 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-1 VH sequence <400> 128 gaagtccaac tggtccaatc cggcgcggag gttaagaagc ccggagaatc gctgaagatc 60 tcatgcaaag ggagcggcta tagctttaca tcatattgga ttggatgggt caggcaaatg 120 ccggggaagg ggctggaatg gatggggaac atttaccctg gggcatcgga tacgcgatac 180 gcacctagct ttcaagggca agtcacaatt tcggcggaca agagcatctc aacggcatac 240 ctgcaatggt cgagcttgaa ggcatctgat actgcaatgt actactgcgc gagactttgg 300 cgggggaata gcttcgacta ctgggggcag ggtaccctgg ttacggtctc gagc 354 <210> 129 <211> 339 <212> DNA <213> Artificial sequence <220> <223> hGBA-1, h-GBA 2, h-GBA 6, h-GBA 8 VL sequence <400> 129 gacattgtga tgacgcaaag ccccgattcg ctggctgtat cgctagggga gcgcgctacg 60 atcaattgca aaagctccca aagcctattg aactcgggaa accaaaagaa ttacttggca 120 tggtatcaac aaaaaccggg gcaaccgccg aagctgctga tctattgggc aagcacccga 180 gagagcggtg tcccggaccg atttagcggg agcggatcgg gcaccgactt cacgctgaca 240 ataagctcat tgcaagccga ggatgtggcg gtctattatt gccaaaacga ctattcatac 300 ccattcacat tcgggcaagg taccaaggtc gagatcaag 339 <210> 130 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-2 VH sequence <400> 130 gaagtccaac tggtccaatc tggagcggaa gtcaagaagc ctggggagag cctgaaaatt 60 tcatgcaagg ggagcggata ttcatttaca agctactgga tcggatgggt ccggcaaatg 120 ccggggaagg gcttggaatg gatgggaaat atataccccg gagacgcgga cacgagatac 180 gcaccgagct ttcaagggca ggtcaccatt agcgctgata aatcgatttc aaccgcatat 240 ctgcaatggt catcgctgaa ggcctccgac accgcgatgt actattgcgc gcggatgtgg 300 cgcggcaata gctttgacta ctgggggcag ggtaccctcg tcacggtctc gagc 354 <210> 131 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 VH sequence <400> 131 gaggtccaac tggtccaaag cggcgcggag gtcaagaagc cgggagaatc cctgaagatt 60 agctgcaaag gctccggcta tagctttaca tcatattgga tcggatgggt cagacaaatg 120 ccgggaaagg gacttgaatg gatggggatc atctatccgg gggcatccga taccaactat 180 gcgccgagct tccaagggca ggtcacgata tccgcggata aatcgattag caccgcatat 240 ctgcaatgga gctcgctgaa ggcatccgac accgcgatgt actactgcgc taggatttgg 300 cgaggaaata gctttgatta ttgggggcag ggtacccttg tcacggtctc gagc 354 <210> 132 <211> 339 <212> DNA <213> Artificial sequence <220> <223> hGBA-3 VL sequence <400> 132 gacattgtca tgacgcaaag ccccgactcg ctggccgtct cactggggga gcgggcgaca 60 gacattgtca tgacgcaaag ccccgactcg ctggccgtct cactggggga gcgggcgaca 60 atcaactgca agagctcgca aagtttgctg aactccggga accaaaagaa ttacctggca 120 atcaactgca agagctcgca aagtttgctg aactccggga accaaaagaa ttacctggca 120 tggtatcaac aaaagccggg gcaacccccg aagctgctga tatattgggc atcaacgcgg 180 tggtatcaac aaaagccggg gcaacccccg aagctgctga tatattgggc atcaacgcgg 180 gaaagcggag tcccggatag atttagcgga tctggatcgg ggaccgactt cacgctgacg 240 gaaagcggag tcccggatag atttagcgga tctggatcgg ggaccgactt cacgctgacg 240 atatctagcc ttcaagccga ggatgtggct gtatattatt gccaaaacga ctactcctat 300 atatctagcc ttcaagccga ggatgtggct gtatattatt gccaaaacga ctactcctat 300 ccgctgacct tcgggcaagg taccaaggtc gagatcaag 339 ccgctgacct tcgggcaagg taccaaggtc gagatcaag 339 <210> 133<210> 133 <211> 354<211> 354 <212> DNA<212> DNA <213> 人工序列<213> Artificial sequence <220> <220> <223> hGBA-4 VH序列 <223> hGBA-4 VH sequence <400> 133 <400> 133 gaagtccaac tagtccaaag cggagccgaa gtcaagaaac cgggggagag ccttaagatc 60 gaagtccaac tagtccaaag cggagccgaa gtcaagaaac cgggggagag ccttaagatc 60 tcatgcaagg ggagcggata ctcatttaca tcatactgga taggatgggt cagacaaatg 120 tcatgcaagg ggagcggata ctcatttaca tcatactgga taggatgggt cagacaaatg 120 cccggcaagg ggctggaatg gatggggatt atataccccg gcgacgctta cactcgatat 180 cccggcaagg ggctggaatg gatggggatt atataccccg gcgacgctta cactcgatat 180 tcgccatcat tccaagggca ggtcacgata tcggccgata aatcgatatc cacggcatac 240 tcgccatcat tccaagggca ggtcacgata tcggccgata aatcgatatc cacggcatac 240 <00??3393> ctgcaatgga gctcactgaa agcatctgat acggcaatgt attattgcac gaggctatgg 300 agggggaata gctttgatgc ctgggggcag ggtaccctgg tcacggtctc gagc 354 <210> 134 <211> 339 <212> DNA <213> Artificial sequence <220> <223> hGBA-4 VL sequence <400> 134 gacatagtta tgacacaatc gccggatagc ctcgcggtca gccttggaga gcgggcgacg 60 atcaactgca agagctccca aagcctattg aactcgggaa atcaaaagaa ttatctgaca 120 tggtatcaac aaaagccggg gcaaccaccg aaactgctga tctattgggc ctcgacaagg 180 gagagcggag tcccggaccg cttctctgga tcgggaagcg ggactgactt cacgctgacc 240 ataagctcgc tgcaagccga ggacgtcgcc gtctattatt gccaaaatga ctactcatac 300 ccgctgacat ttggccaagg taccaaggtc gagatcaag 339 <210> 135 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-5 VH sequence <400> 135 gaggtgcaac tggtacaatc cggggcggaa gtgaagaagc cgggggaatc gctgaagata 60 agctgcaaag gctctggata tagctttacg agctactgga tcggatgggt caggcaaatg 120 ccggggaagg gactggaatg gatggggata atataccccg gagcggcata cacgagatat 180 gcgccgagct tccaagggca agtgacaata agcgcggaca aatcgattag cacggcatat 240 ctgcaatggt cctcgctgaa ggcgagcgat accgcaatgt actattgcgc gagactatgg 300 cgcgggaact catttgatta ctgggggcag ggtaccctag tgacggtctc gagc 354 <210> 136 <211> 339 <212> DNA[[ID=?]] <213> Artificial sequence <220> <223> hGBA-5 VL sequence <400> 136 gacattgtca tgacgcaaag cccggatagc ctggctgtat cgctggggga gagagcgacg 60 atcaactgca aatcatcgca atcattgcta aattcgggga accaaaagaa ttatttggca 120 tggtatcaac aaaagccggg gcaaccgccg aaactgctga tttactgggc atccacgaga 180 gaatcgggag tcccggaccg atttagcgga tctgggagcg ggaccgattt cacgctgacc 240 It should be noted that there seems to be an error in the tag "[[ID=?]]" in the original text, which is likely a mislabeling. It should probably be something like "". This might cause some confusion in the translation and understanding of the text's structure. If possible, it would be beneficial to correct the original text for more accurate processing.attagctcgc tgcaagcgga ggatgtggcg gtctattact gccaacaaga ttattcatac 300 ccatttacat ttgggcaagg taccaaggtc gagatcaag 339 <210> 137 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-6 VH sequence <400> 137 gaagtacaat tggttcaatc gggggccgaa gtcaagaagc cgggggaatc gctgaagata 60 tcctgcaagg ggagcggata tacatttaca tcttactgga tcggatgggt cagacaaatg 120 cccggaaagg ggcttgaatg gatggggaac atttatcctg gcgcgagcta tacgcgctat 180 agcccgagct tccaagggca ggtcacgatt agcgccgaca agagcatttc gacggcatac 240 ctgcaatgga gctcgctgaa agcatcggat acggcaatgt attactgcac ccggcaatgg 3​​​​​​​​​​​​​​​​​gaagttcaat tggtccaatc tggagccgaa gtcaagaagc ccggagaatc gctgaagatt 60 gaagttcaat tggtccaatc tggagccgaa gtcaagaagc ccggagaatc gctgaagatt 60 agctgcaagg ggagcggata ttcctttaca tcatactgga tcggctgggt cagacaaatg 120 agctgcaagg ggagcggata ttcctttaca tcatactgga tcggctgggt cagacaaatg 120 cccggaaagg gactggaatg gatggggaac atatatcccg gagaagccta tacgagatac 180 cccggaaagg gactggaatg gatggggaac atatatcccg gagaagccta tacgagatac 180 tcgccatcat ttcaaggaca ggtcaccata agcgcggaca agagcataag caccgcatac 240 tcgccatcat ttcaaggaca ggtcaccata agcgcggaca agagcataag caccgcatac 240 ctgcaatgga gctcgctgaa ggcatcggac accgccatgt attactgcac gcgactatgg 300 ctgcaatgga gctcgctgaa ggcatcggac accgccatgt attactgcac gcgactatgg 300 aggggaaata gctttgacta ttgggggcag ggtaccttag tcacggtctc gagc 354 aggggaaata gctttgacta ttgggggcag ggtaccttag tcacggtctc gagc 354 <210> 139<210> 139 <211> 339<211> 339 <212> DNA<212> DNA <213> 人工序列<213> Artificial sequence <220> <220> <223> hGBA-7 VL序列 <223> hGBA-7 VL sequence <400> 139 <400> 139 gatatagtaa tgactcaatc acccgatagc ttggctgtga gcctgggaga aagagctaca 60 gatatagtaa tgactcaatc acccgatagc ttggctgtga gcctgggaga aagagctaca 60 atcaactgca agagctccca atcagtcctg aactctggga atcaaaagaa ttacctgaca 120 atcaactgca agagctccca atcagtcctg aactctggga atcaaaagaa ttacctgaca 120 tggtatcaac aaaagcccgg acaaccgccg aagctgctga tctactgggc gagcacgagg 180 tggtatcaac aaaagcccgg acaaccgccg aagctgctga tctactgggc gagcacgagg 180 gagagcggag tcccggatcg attttctggc tccgggagcg gaaccgactt cacactgact 240 gagagcggag tcccggatcg attttctggc tccgggagcg gaaccgactt cacactgact 240 attagctcgc tgcaagcgga ggacgtcgcc gtctactatt gccaaaatga ttattcatac 300 cccttcacat ttgggcaagg taccaaggtc gagatcaag 339 <210> 140 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-8 VH sequence <400> 140 gaggtgcaac tagtgcaatc gggggccgaa gtgaagaaac ctggggaatc gctgaagata 60 tcatgcaagg ggagcggata ctcctttaca tcatattgga tcggatgggt caggcaaatg 120 ccggggaagg ggctggaatg gatgggaaac atatatccga gcgaatcata tacgaactac 180 gcgccgagct ttcaaggaca agtcacgata tccgcggata aatcgatatc gaccgcatac 240 ctgcaatgga gctcgctgaa ggcttccgac actgcgatgt attactgcac gaggctatgg 300 agggggaata gcttcgacta ttgggggcag ggtaccctgg tgacggtctc gagc 354 <210> 141 <211> 354 <212> DNA <213> Artificial sequence <220> <223> hGBA-9 VH sequence <400> 141 gaagtccaat tagtccaatc gggggccgag gtcaagaagc cgggggaatc gctcaagata 60 agctgcaagg gatcgggata tacattcacg agctactgga taggatgggt caggcaaatg 120 ccggggaagg ggctggaatg gatgggaatc atatatcctt ccgcggcata tacgcgatat 180 gcgccatcat ttcaaggaca ggtcacgata agcgccgaca agagcattag caccgcatac 240 ctgcaatggt cgagccttaa ggcatcggac accgcgatgt actactgcac gcggatgtgg 300 aggggaaata gctttgatta ctgggggcag ggtaccctag tcacggtctc gagc 354 <210> 142 <211> 339 <212> DNA <213> Artificial sequence [[ID=D20]]<220> <223> hGBA-9 VL sequence <400> 142 gacatcgtca tgacgcaaag cccggactcg ctggcggtct cgctggggga gcgggccaca 60 ataaattgca agagctcgca atcggtcctg aatagcggga accaaaagaa ttatctggcc 120 tggtatcaac aaaagccggg gcaaccaccg aagctgctaa tctattgggc gagcacgagg 180 gagagcggag tccccgatcg atttagcgga tcgggaagcg ggaccgattt cacgctgacg 240 atttcgagcc tacaagccga ggatgtggcg gtctattact gccaacaaga ctactcatac 300 ccatttacat ttggacaagg taccaaggtc gagatcaag 339 <210> 143 <211> 7 <212> PRT <213> Artificial sequence <220> <223> RLPXTGG Tags <220> <221> MISC_FEATURE <222> (4)..(4) <223> X is any of the 20 naturally occurring amino acids <400> 143 Arg Leu Pro Xaa Thr Gly Gly 1 5 <210> 144 <211> 11 <212> PRT <213> Artificial sequence <220> <223> GGGGSLPXTGG Tags <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is any of the 20 naturally occurring amino acids <400> 144 Gly Gly Gly Gly Ser Leu Pro Xaa Thr Gly Gly 1 5 10

Claims

1. An antibody or fragment thereof that binds to CLDN18.2, comprising: a. HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 18, respectively, and LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5, and SEQ ID NO: 29, respectively; b. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 7, SEQ ID NO: 10 and SEQ ID NO: 19, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; f. HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO: 8, SEQ ID NO: 14 and SEQ ID NO: 22, respectively, and LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively; or h. The HCDR1, HCDR2 and HCDR3 sequences are SEQ ID NO: 7, SEQ ID NO: 16 and SEQ ID NO: 23, respectively, and the LCDR1, LCDR2 and LCDR3 sequences are SEQ ID NO: 25, SEQ ID NO: 5 and SEQ ID NO: 29, respectively.

2. The antibody or fragment thereof according to claim 1, comprising: a. a VH sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 32; b. a VH sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 34; f. a VH sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 41; or h. a VH sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 44; as well as j. A VL sequence that has at least 90% sequence identity to the amino acid sequence of SEQ ID NO:

33.

3. The antibody or fragment thereof according to claim 1, comprising: a. VH sequence of SEQ ID NO: 32 and VL sequence of SEQ ID NO: 33; b. VH sequence of SEQ ID NO: 34 and VL sequence of SEQ ID NO: 33; f. the VH sequence of SEQ ID NO: 41 and the VL sequence of SEQ ID NO: 33; or h. VH sequence of SEQ ID NO:44 and VL sequence of SEQ ID NO:

33.

4. The antibody or fragment thereof according to claim 1, consisting of: a. a heavy chain sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 49, and a light chain sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 50; b. a heavy chain sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 51, and a light chain sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 50; f. a heavy chain sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 58, and a light chain sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 50; or h. a heavy chain sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 61, and a light chain sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:

50.

5. The antibody or fragment thereof of claim 1 , wherein the form of the antibody or fragment thereof is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, synthetic IgG, IgM, F(ab)2, scFv, IgGACH2, F(ab')2, scFvCH3, Fab, scFv4, scFv3, scFv2, dsFv, Fv, scFv-Fc, (scFv)2, non-depleted IgG, diabodies and bivalent antibodies, or Fc-engineered versions thereof.

6. The antibody or fragment thereof according to claim 1, wherein the antibody or fragment thereof (i) humanized; (ii) is separate; and / or (iii) does not bind to CLDN18.

1.

7. The antibody or fragment thereof according to any one of claims 1 to 6, wherein the antibody or fragment thereof exhibits enhanced binding to CLDN18.2 compared to a reference antibody, wherein the reference antibody comprises the heavy chain sequence of SEQ ID NO: 47 and the light chain sequence of SEQ ID NO:

48.

8. The antibody or fragment thereof according to claim 7, wherein (i) the measured EC50 value of the antibody is at least 10% lower than the EC50 value of a reference antibody; and / or (ii) the measured maxMFI value of the antibody is at least 10% higher than the maxMFI value of a reference antibody; wherein the reference antibody comprises a heavy chain sequence of SEQ ID NO: 47 and a light chain sequence of SEQ ID NO:

48.

9. A nucleic acid encoding the antibody or fragment thereof according to any one of claims 1 to 8.

10. A vector comprising the nucleic acid according to claim 9.

11. A host cell comprising the nucleic acid of claim 9 or the vector of claim 10.

12. Use of the antibody or fragment thereof according to any one of claims 1 to 8, the nucleic acid according to claim 9, the vector according to claim 10 or the host cell according to claim 11 in the preparation of a medicament for treating pancreatic cancer and / or gastric cancer in a subject.

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