Method for specifically eliminating adipocytes presenting perilipin-1 fragments

Abstract

The present invention relates to antigen-binding peptides that specifically bind to at least one perilipin-1 epitope as defined herein. The present invention also relates to antigen-binding peptides for the prevention or treatment of obesity. In addition, the present invention relates to bispecific antigen-binding peptides and their uses, the bispecific antigen-binding peptides comprising a first binding site that specifically binds to a perilipin-1 epitope and a second binding site. The present invention also relates to a pharmaceutical composition comprising an antigen-binding peptide or a bispecific antigen-binding peptide, the pharmaceutical composition being for the prevention or treatment of obesity. The present invention also relates to an isolated nucleic acid encoding an antigen-binding peptide or a bispecific antigen-binding peptide. In addition, the present invention relates to a recombinant cell comprising the nucleic acid and a method of producing a means for specifically targeting adipocytes presenting a perilipin-1 fragment.

Description

Technical Field

[0001] The present invention relates to antigen-binding peptides that specifically bind to at least one perilipin-1 epitope as defined herein. The present invention further relates to antigen-binding peptides for preventing or treating obesity. In addition, the present invention relates to bispecific antigen-binding peptides and their uses, the bispecific antigen-binding peptides comprising a first binding site that specifically binds to a perilipin-1 epitope and a second binding site. The present invention also relates to pharmaceutical compositions comprising the antigen-binding peptides or bispecific antigen-binding peptides for preventing or treating obesity. The present invention further relates to isolated nucleic acids encoding the antigen-binding peptides or bispecific antigen-binding peptides. In addition, the present invention relates to recombinant cells comprising the nucleic acids and methods of producing means for specifically targeting adipocytes presenting perilipin-1 fragments. Background Art

[0002] Obesity is a worldwide problem and, according to the World Health Organization, more than 1.9 billion people are overweight. People suffering from obesity are generally prone to various medical conditions. Surgical interventions are currently a successful treatment method; however, complications usually arise along with subsequent gastrointestinal problems. Therefore, surgical interventions are only considered acceptable in highly obese patients with high comorbidities. Due to the severe side effect profiles, relatively promising pharmaceutical therapies have had to be withdrawn from the market. The pleiotropic nature of the signaling mechanisms involved causes unacceptable side effects. Thus, there is a lack of treatment methods that are successful in the long term and have negligible side effects.

[0003] The long-term harmful effects of excessive body fat are well known. However, there are also medical conditions that lead to body fat loss, namely lipodystrophy. Although the metabolic complications vary with the degree of fat loss, common consequences of lipodystrophy are insulin resistance or diabetes, non-ketosis, increased metabolic rate, hyperlipidemia, and hepatomegaly including fatty liver. These effects are due to the lack of metabolically active adipocytes, regardless of the underlying cause of adipocyte loss, as shown in various animal models. Lipodystrophy has been widely noted as a common side effect of some antiretroviral drugs that cause partial redistribution of fat.

[0004] Perilipin-1 is specifically expressed in adipocytes, but not in other cells that store triacylglycerol, such as hepatocytes [1]. In these other cells, other members of the lipid droplet-associated proteins, such as adipophilin and TIP47, are present instead of perilipin-1. Since perilipin-1 protects the lipid storage droplets in adipocytes from the activity of lipolytic enzymes, any mechanism that results in the depletion of perilipin-1 associated with the lipid storage droplets may lead to an increase in lipolysis and the release of lipids stored in the droplets (thereby worsening the metabolic condition). Therefore, a reduction in fat mass is expected at the expense of an adverse metabolic condition. The adverse metabolic condition can be prevented by completely eliminating the adipocytes. Since perilipin-1 is absent in other types of lipid storage cells, targeting perilipin-1 to activate the immune effector mechanism against adipocytes can allow for the specific elimination of adipocytes. WO 02 / 028410A1 discloses that perilipin can be a target for regulating body weight, muscle mass, and diabetes. Greenberg et al. (Journal of Biological Chemistry, 1991, Vol. 266, No. 17, pp. 11341-11346) described perilipin-1 and disclosed that it is present intracellularly on the surface of lipid droplets, such as lipid storage droplets, in adipocytes.

[0005] An autoimmune response against adipocytes leads to almost complete loss of adipose tissue, as observed in generalized acquired lipodystrophy (AGL) [2]. Extensive clinical evidence of an autoimmune etiology exists in most cases of typical acquired lipodystrophy. Serum autoantibodies against adipose tissue have been found in patients with acquired generalized lipodystrophy [2]. In particular, autoantibodies against perilipin-1 have been found to be associated with acquired generalized lipodystrophy [3].

[0006] Therefore, the effector system that causes fat loss in lipodystrophy patients can be used to specifically target adipose tissue in patients with obesity. However, no such specific effector system has been provided, which could be, for example, an antibody or an antigen-binding fragment, or a cytotoxic T cell. In particular, despite many efforts, no adipocyte-specific epitope that could potentially serve as a specific therapeutic target has been identified to date [4].

[0007] Therefore, an object of the present invention is to provide methods for specifically targeting and / or eliminating adipocytes, such as antigen-binding peptides or cytotoxic T cells. In addition, an object of the present invention is to provide methods for generating means for specifically targeting adipocytes. Summary of the Invention

[0008] The present invention relates to epitopes of perilipin-1, which are molecular target structures that specifically target and / or eliminate adipocytes. In particular, the epitopes disclosed herein are target structures of the intracellular protein perilipin-1 that are presented on the surface of adipocytes. Antigen-binding peptides that target the epitopes disclosed herein can be used alone or in combination with any therapeutic agent to target and / or eliminate adipocytes by activating an immune effector system such as an exogenous effector system or an endogenous effector system. The epitopes disclosed herein can also be used to generate perilipin-1-specific cytotoxic T cells that are capable of targeting adipocytes presenting fragments of perilipin-1.

[0009] The inventors have disclosed perilipin-1 as an autoantigen targeted by autoantibodies from sera of AGL patients. In addition, the inventors have disclosed various epitopes of perilipin-1 having any one of SEQ ID No: 1-6, 330-333, and provided antibodies and antigen-binding fragments that target said epitopes, which can be used to treat obesity. The inventors have surprisingly found that perilipin-1 and / or its fragments are present on the surface of adipocytes, rather than merely coating or surrounding intracellular lipid droplets such as lipid storage droplets within such adipocytes. Without wishing to be bound by any theory, the inventors have found that perilipin-1 and / or its fragments are presented or otherwise present on the surface of adipocytes and can thus be specifically targeted.

[0010] The present invention also relates to methods for specifically targeting adipocytes. These methods for specifically targeting adipocytes can be used to treat or prevent obesity-related diseases and / or medical conditions.

[0011] The present invention aims to specifically target and / or eliminate adipocytes using exogenous or endogenous effector systems of the immune system. Such exogenous effector systems can be, for example, antibodies and / or cytotoxic T cells generated and / or amplified ex vivo or in vitro. Epitopes of perilipin-1 are disclosed herein, which are SEQ ID NO:1-6, 330-333, allowing for the specific targeting of adipocytes by fragments of perilipin-1 presented on said adipocytes, particularly on the surface of said adipocytes. The adipocytes are labeled for effector systems such as the complement system by targeting the adipocytes via an antigen-binding peptide specific for any of SEQ ID NO:1-6, 330-333 via perilipin-1, which results in the activation of the complement system, and / or activation of Fc receptors such as FcRIII (CD16), Fc-RII (CD32), Fc-RI (CD64) or others, which results in the recruitment and activation of effector systems such as ADCC (antibody-dependent cell cytotoxicity) by NK (natural killer) cells or ADCP (antibody-dependent cell phagocytosis) by macrophages, neutrophils, or any other effector system carrying the corresponding Fc receptor. The recruitment of one of these effector systems thus leads to the targeting and / or elimination of the adipocytes. Alternatively, the adipocytes can be directly targeted by cytotoxic T cells specific for perilipin-1, particularly cytotoxic T cells specific for any of SEQ ID NO:1-6, 330-333, which then eliminate the adipocytes presenting at least one of those perilipin-1 epitopes. Thus, the means for specifically targeting and / or eliminating adipocytes according to the present invention can directly eliminate the adipocytes in the case of ADCP and is thus a direct elimination means, or can indirectly eliminate the adipocytes by targeting the adipocytes to cause the activation of effector systems such as the complement system or ADCC or cytotoxic T cells and is thus an indirect elimination means.

[0012] The cell type specificity of the effector response is ensured by the specificity of the cellular antigen, i.e., perilipin-1, particularly epitopes having the amino acid sequence according to any of SEQ ID NO:1-6, 330-333. Thus, the present invention provides methods for specifically targeting and / or eliminating adipocytes without off-target effects on other cells and thus with only negligible side effects.

[0013] Furthermore, targeting adipocytes of the immune effector system using antigen-binding peptides allows for systemic application, for example, by infusion, and / or allows for fine-tuning of the targeted administration to eliminate certain fat depots by administration into the corresponding fat depots (such as by injection into the target fat depot).

[0014] The present invention uses adipocyte - specific presentation of fragments of typical intracellular proteins, i.e., presentation of proteins that have hitherto been known to exist only intracellularly, on the surface of adipocytes, namely perilipin - 1 fragments. Perilipin - 1 is essential for lipid storage in adipocytes. The inventors herein disclose six peptide sequences that are epitopes on perilipin - 1, which were identified by analyzing the binding patterns of anti - perilipin - 1 autoantibodies from patients with lipodystrophy. The inventors further disclose peptide sequences that are variants of these epitopes, where the variants of the epitopes contain additional residues, and the additional residues can equally well serve as epitopes. The multiple identified epitopes are highly conserved in the perilipin - 1 sequences of mice and humans.

[0015] The target antigenic epitopes of perilipin - 1 disclosed herein allow for:

[0016] a) immunizing an animal with the target construct to generate polyclonal or monoclonal antibodies and / or antigen - binding fragments against the perilipin - 1 peptide presented by adipocytes,

[0017] b) screening a recombinant antibody library and / or a small - molecule library to identify specific antibodies, antigen - binding fragments, or other suitable affinity ligands against the perilipin - 1 peptide presented by adipocytes, and / or

[0018] c) isolating and / or generating cytotoxic T cells in vitro that are specific for the perilipin - 1 peptide presented by adipocytes.

[0019] Using the antibodies, antibody fragments, or other suitable affinity ligands produced by the methods according to a) or b), a specific immune effector response can be induced by labeling the adipocytes in vivo. In addition, using the cytotoxic T cells produced by the method according to c), adipocytes can be indirectly eliminated in vivo.

[0020] Hereinafter, the elements of the present invention will be described. These elements are listed together with the specific embodiments. However, it should be understood that these elements can be combined in any way and in any number to produce additional embodiments. The various described examples and preferred embodiments should not be construed as limiting the present invention to the specifically described embodiments. The description should be understood to support and cover combinations of two or more specifically described embodiments or combinations of one or more specifically described embodiments with any number of the disclosed and / or preferred elements. In addition, unless the context otherwise indicates, any arrangement and combination of all the described elements in this application should be considered to be disclosed by the description of this application.

[0021] In a first aspect, the present invention relates to an antigen-binding peptide that specifically binds to at least one perilipin-1 epitope selected from the following amino acid sequences: LTLLDGDLPE (SEQ ID NO:1), EKIASELK (SEQ ID NO:2), VPIASTSDKV (SEQ ID NO:3), PAPGHQQAQK (SEQ ID NO:4), PSLLSRVGALTN (SEQ ID NO:5), and PWLHSLAA (SEQ ID NO:6). In one embodiment, the at least one perilipin-1 epitope is selected from the following amino acid sequences: NKGLTLLDGDLPEQE (SEQ ID NO:330), QYPPEKIASELKDTI (SEQ ID NO:331), AKPSLLSRVGALTNT (SEQ ID NO:332), and EVRVPWLHSLAAAQE (SEQ ID NO:333).

[0022] In one embodiment, the antigen-binding peptide binds to more than two of SEQ ID NO:1-6 and SEQ ID NO:330-333.

[0023] In one embodiment, the perilipin-1 epitope is a human perilipin-1 epitope.

[0024] In one embodiment, the antigen-binding peptide is not an autoantibody targeting perilipin-1 from a human patient with lipodystrophy, and wherein the antigen-binding peptide is preferably not an anti-PLIN1 antibody targeting perilipin-1, the anti-PLIN1 antibody being directed against a peptide spanning Thr8-Ala145 with catalog number #AF6615 from manufacturer R&D.

[0025] In one embodiment, the antigen-binding peptide competes with an autoantibody targeting perilipin-1 from a human patient with lipodystrophy for binding.

[0026] In one embodiment, the antigen-binding peptide has an affinity (K -4 ) of at least 10 D M for binding to perilipin-1.

[0027] In one embodiment, the antigen-binding peptide is an antibody, preferably a monoclonal antibody.

[0028] In one embodiment, the antigen-binding peptide is a polyclonal antibody.

[0029] In one embodiment, the antigen-binding peptide, in particular the antibody, when incubated with 3T3-L1 cells that have differentiated into adipocytes in the presence of complement, causes complement-mediated cell death of the 3T3-L1 cells and / or the differentiated adipocytes.

[0030] In one embodiment, the complement-mediated cell death is determined, preferably by numerically determining the ratio of live cells to dead cells, using a suitable dye or dye mixture such as a fluorescent dye or a fluorescent dye mixture. Generally, such a dye or dye mixture differentiates between live cells and dead cells. An example of such a dye mixture is the "FluoroQuench TM Staining / Quenching Reagent" dye, which is commercially available from ThermoFisher. Preferably, the 3T3-L1 cells have been differentiated into adipocytes using a suitable differentiation medium (such as serum-free differentiation (SFD) medium, supplemented with insulin and optionally further supplemented with dexamethasone and / or isobutyl-1-methylxanthine).

[0031] In one embodiment, the complement is selected from mammalian complement, preferably human complement or rodent complement. In one embodiment, the rodent complement is rabbit complement or mouse complement. Complement can be commercially obtained from various companies such as BAG Diagnostics GmbH, BAG Health Care or Bio-Rad. Alternatively, serum or plasma can be used as a source of complement.

[0032] In one embodiment, the antigen-binding peptide, in particular the antibody, binds to the surface of the adipocyte when the antigen-binding peptide, in particular the antibody, is incubated with the adipocyte. In one embodiment, binding of the corresponding antigen-binding peptide, preferably the corresponding antibody, to the adipocyte is detected by incubating the adipocyte with the corresponding antigen-binding peptide, preferably the corresponding antibody, and then using a suitable detection technique (such as separate immunochemical detection or in combination with flow cytometry).

[0033] As used herein, the "surface" of the adipocyte generally refers to the outer surface of such an adipocyte, i.e., the extracellular surface that is exposed to the surroundings of the adipocyte.

[0034] In one embodiment, the antigen-binding peptide, in particular the antibody, when incubated with 3T3-L1 cells that have differentiated into adipocytes in the presence of complement, causes complement-mediated cell death of the 3T3-L1 cells and / or the differentiated adipocytes, and likewise, the antigen-binding peptide, in particular the antibody, binds to the surface of the adipocyte when incubated with the adipocyte.

[0035] In one embodiment, the antigen-binding peptide is an antigen-binding peptide comprising the following, preferably an antibody, and the following are:

[0036] i. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 19, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 22, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 23; or

[0037] ii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 25, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 26, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 28, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 29; or

[0038] iii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 30, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 31, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 32, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 33, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 34, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 35; or

[0039] iv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 36, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 37, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 38, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 39, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 40, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 41; or

[0040] v. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:42, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:43, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:44, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:45, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:46, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:47; or

[0041] vi. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:48, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:49, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:50, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:51, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:52, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:53; or

[0042] vii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:54, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:55, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:56, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:57, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:58, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:59; or

[0043] viii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:60, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:61, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:62, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:63, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:64, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:65; or

[0044] ix. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:66, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:67, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:68, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:69, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:70, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:71; or

[0045] x. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:72, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:73, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:74, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:75, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:76, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:77; or

[0046] xi. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:78, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:79, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:80, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:81, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:82, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:83; or

[0047] xii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:84, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:85, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:86, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:87, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:88, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:89; or

[0048] xiii. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:90, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:91, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:92, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:93, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:94, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:95; or

[0049] xiv. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:96, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:97, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:98, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:99, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:100, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:101; or

[0050] xv. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:102, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:103, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:104, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:105, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:106, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:107; or

[0051] xvi. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:108, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:109, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:110, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO:111, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO:112, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO:113; or

[0052] xvii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 114, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 115, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 116, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 117, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 118, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 119; or

[0053] xviii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 120, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 121, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 122, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 123, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 124, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 125; or

[0054] xix. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 126, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 127, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 128, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 129, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 130, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 131; or

[0055] xx. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 132, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 133, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 134, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 135, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 136, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 137; or

[0056] xxi. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 138, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 139, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 140, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 141, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 142, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 143; or

[0057] xxii. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 144, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 145, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 146, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 147, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 148, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 149; or

[0058] xxiii. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 150, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 151, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 152, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 153, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 154, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 155; or

[0059] xxiv. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 156, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 157, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 158, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 159, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 160, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 161; or

[0060] xxv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:162, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:163, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:164, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:165, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:166, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:167; or

[0061] xxvi. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:168, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:169, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:170, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:171, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:172, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:173; or

[0062] xxvii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:174, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:175, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:176, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:177, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:178, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:179; or

[0063] xxviii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:180, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:181, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:182, a light chain CDR1 region comprising the amino acid sequence of SEQ IDNO:183, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:184, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:185; or

[0064] xxix. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 186, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 187, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 188, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 189, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 190, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 191; or

[0065] xxx. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 192, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 193, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 194, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 195, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 196, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 197; or

[0066] xxxi. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 198, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 199, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 200, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 201, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 202, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 203; or

[0067] xxxii. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 204, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 205, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 206, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 207, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 208, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 209; or

[0068] xxxiii. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 210, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 211, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 212, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 213, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 214, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 215; or

[0069] xxxiv. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 216, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 217, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 218, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 219, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 220, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 221; or

[0070] xxxv. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 222, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 223, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 224, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 225, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 226, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 227; or

[0071] xxxvi. The heavy-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 228, the heavy-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 229, the heavy-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 230, the light-chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 231, the light-chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 232, and the light-chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 233; or

[0072] xxxvii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 234, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 235, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 236, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 237, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 238, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 239; or

[0073] xxxviii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 240, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 241, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 242, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 243, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 244, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 245; or

[0074] xxxix. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 246, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 247, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 248, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 249, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 250, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 251; or

[0075] xl. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 252, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 253, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 254, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 255, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 256, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 257; or

[0076] xli. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:258, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:259, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:260, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:261, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:262, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:263; or

[0077] xlii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:264, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:265, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:266, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:267, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:268, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:269; or

[0078] xliii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:270, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:271, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:272, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:273, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:274, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:275; or

[0079] xliv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:276, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:277, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:278, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:279, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:280, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:281; or

[0080] xlv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 282, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 283, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 284, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 285, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 286, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 287; or

[0081] xlvi. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 288, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 289, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 290, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 291, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 292, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 293; or

[0082] xlvii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 294, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 295, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 296, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 297, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 298, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 299; or

[0083] xlviii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 300, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 301, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 302, a light chain CDR1 region comprising the amino acid sequence of SEQ IDNO: 303, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 304, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 305; or

[0084] xlix. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 306, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 307, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 308, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 309, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 310, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 311; or

[0085] 1. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 312, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 313, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 314, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 315, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 316, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 317; or

[0086] li. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 318, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 319, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 320, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 321, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 322, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 323; or

[0087] lii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 324, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 325, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 326, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 327, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 328, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 329;

[0088] Or wherein the antigen-binding peptide is a peptide, preferably an antibody, and the heavy chain CDR1 region, CDR2 region, CDR3 region and the light chain CDR1 region, CDR2 region, CDR3 region comprise amino acid sequences having at least 90% identity, preferably at least 95% identity, more preferably at least 98% identity, even more preferably 99% identity with any of the sequences shown in i.-lii.

[0089] In one embodiment, the antigen-binding peptide is an antigen-binding peptide comprising each of the following, preferably an antibody, and each of the following is:

[0090] i. Comprising the amino acid sequence of SEQ ID NO: 334 and / or comprising the amino acid sequence of SEQ ID NO: 335; or

[0091] ii. Comprising the amino acid sequence of SEQ ID NO: 336 and / or comprising the amino acid sequence of SEQ ID NO: 337; or

[0092] iii. Comprising the amino acid sequence of SEQ ID NO: 338 and / or comprising the amino acid sequence of SEQ ID NO: 339; or

[0093] iv. Comprising the amino acid sequence of SEQ ID NO: 340 and / or comprising the amino acid sequence of SEQ ID NO: 341; or

[0094] v. Comprising the amino acid sequence of SEQ ID NO: 342 and / or comprising the amino acid sequence of SEQ ID NO: 343; or

[0095] vi. Comprising the amino acid sequence of SEQ ID NO: 344 and / or comprising the amino acid sequence of SEQ ID NO: 345; or

[0096] vii. Comprising the amino acid sequence of SEQ ID NO: 346 and / or comprising the amino acid sequence of SEQ ID NO: 347; or

[0097] viii. Comprising the amino acid sequence of SEQ ID NO: 348 and / or comprising the amino acid sequence of SEQ ID NO: 349; or

[0098] ix. Comprising the amino acid sequence of SEQ ID NO: 350 and / or comprising the amino acid sequence of SEQ ID NO: 351; or

[0099] x. Comprising the amino acid sequence of SEQ ID NO: 352 and / or comprising the amino acid sequence of SEQ ID NO: 353; or

[0100] xi. Comprising the amino acid sequence of SEQ ID NO: 354 and / or comprising the amino acid sequence of SEQ ID NO: 355; or

[0101] xii. Comprising the amino acid sequence of SEQ ID NO: 356 and / or comprising the amino acid sequence of SEQ ID NO: 357; or

[0102] xiii. Comprising the amino acid sequence of SEQ ID NO:358 and / or comprising the amino acid sequence of SEQ ID NO:359; or

[0103] xiv. Comprising the amino acid sequence of SEQ ID NO:360 and / or comprising the amino acid sequence of SEQ ID NO:361; or

[0104] xv. Comprising the amino acid sequence of SEQ ID NO:362 and / or comprising the amino acid sequence of SEQ ID NO:363; or

[0105] xvi. Comprising the amino acid sequence of SEQ ID NO:364 and / or comprising the amino acid sequence of SEQ ID NO:365; or

[0106] xvii. Comprising the amino acid sequence of SEQ ID NO:366 and / or comprising the amino acid sequence of SEQ ID NO:367; or

[0107] xviii. Comprising the amino acid sequence of SEQ ID NO:368 and / or comprising the amino acid sequence of SEQ ID NO:369; or

[0108] xix. Comprising the amino acid sequence of SEQ ID NO:370 and / or comprising the amino acid sequence of SEQ ID NO:371; or

[0109] xx. Comprising the amino acid sequence of SEQ ID NO:372 and / or comprising the amino acid sequence of SEQ ID NO:373; or

[0110] xxi. Comprising the amino acid sequence of SEQ ID NO:374 and / or comprising the amino acid sequence of SEQ ID NO:375; or

[0111] xxii. Comprising the amino acid sequence of SEQ ID NO:376 and / or comprising the amino acid sequence of SEQ ID NO:377; or

[0112] xxiii. Comprising the amino acid sequence of SEQ ID NO:378 and / or comprising the amino acid sequence of SEQ ID NO:379; or

[0113] xxiv. Comprising the amino acid sequence of SEQ ID NO:380 and / or comprising the amino acid sequence of SEQ ID NO:381; or

[0114] xxv. Comprising the amino acid sequence of SEQ ID NO:382 and / or comprising the amino acid sequence of SEQ ID NO:383; or

[0115] xxvi. Comprising the amino acid sequence of SEQ ID NO: 384 and / or comprising the amino acid sequence of SEQ ID NO: 385; or

[0116] xxvii. Comprising the amino acid sequence of SEQ ID NO: 386 and / or comprising the amino acid sequence of SEQ ID NO: 387; or

[0117] xxviii. Comprising the amino acid sequence of SEQ ID NO: 388 and / or comprising the amino acid sequence of SEQ ID NO: 389; or

[0118] xxix. Comprising the amino acid sequence of SEQ ID NO: 390 and / or comprising the amino acid sequence of SEQ ID NO: 391; or

[0119] xxx. Comprising the amino acid sequence of SEQ ID NO: 392 and / or comprising the amino acid sequence of SEQ ID NO: 393; or

[0120] xxxi. Comprising the amino acid sequence of SEQ ID NO: 394 and / or comprising the amino acid sequence of SEQ ID NO: 395; or

[0121] xxxii. Comprising the amino acid sequence of SEQ ID NO: 396 and / or comprising the amino acid sequence of SEQ ID NO: 397; or

[0122] xxxiii. Comprising the amino acid sequence of SEQ ID NO: 398 and / or comprising the amino acid sequence of SEQ ID NO: 399; or

[0123] xxxiv. Comprising the amino acid sequence of SEQ ID NO: 400 and / or comprising the amino acid sequence of SEQ ID NO: 401; or

[0124] xxxv. Comprising the amino acid sequence of SEQ ID NO: 402 and / or comprising the amino acid sequence of SEQ ID NO: 403; or

[0125] xxxvi. Comprising the amino acid sequence of SEQ ID NO: 404 and / or comprising the amino acid sequence of SEQ ID NO: 405; or

[0126] xxxvii. Comprising the amino acid sequence of SEQ ID NO: 406 and / or comprising the amino acid sequence of SEQ ID NO: 407; or

[0127] xxxviii. Comprising the amino acid sequence of SEQ ID NO: 408 and / or comprising the amino acid sequence of SEQ ID NO: 409; or

[0128] xxxix. Comprising the amino acid sequence of SEQ ID NO: 410 and / or comprising the amino acid sequence of SEQ ID NO: 411; or

[0129] xl. Comprising the amino acid sequence of SEQ ID NO: 412 and / or comprising the amino acid sequence of SEQ ID NO: 413; or

[0130] xli. Comprising the amino acid sequence of SEQ ID NO: 414 and / or comprising the amino acid sequence of SEQ ID NO: 415; or

[0131] xlii. Comprising the amino acid sequence of SEQ ID NO: 416 and / or comprising the amino acid sequence of SEQ ID NO: 417; or

[0132] xliii. Comprising the amino acid sequence of SEQ ID NO: 418 and / or comprising the amino acid sequence of SEQ ID NO: 419; or

[0133] xliv. Comprising the amino acid sequence of SEQ ID NO: 420 and / or comprising the amino acid sequence of SEQ ID NO: 421; or

[0134] xlv. Comprising the amino acid sequence of SEQ ID NO: 422 and / or comprising the amino acid sequence of SEQ ID NO: 423; or

[0135] xlvi. Comprising the amino acid sequence of SEQ ID NO: 424 and / or comprising the amino acid sequence of SEQ ID NO: 425; or

[0136] xlvii. Comprising the amino acid sequence of SEQ ID NO: 426 and / or comprising the amino acid sequence of SEQ ID NO: 427; or

[0137] xlviii. Comprising the amino acid sequence of SEQ ID NO: 428 and / or comprising the amino acid sequence of SEQ ID NO: 429; or

[0138] xlix. Comprising the amino acid sequence of SEQ ID NO: 430 and / or comprising the amino acid sequence of SEQ ID NO: 431; or

[0139] 1. Comprising the amino acid sequence of SEQ ID NO: 432 and / or comprising the amino acid sequence of SEQ ID NO: 433; or

[0140] li. Comprising the amino acid sequence of SEQ ID NO: 434 and / or comprising the amino acid sequence of SEQ ID NO: 435; or

[0141] lii. Comprising the amino acid sequence of SEQ ID NO: 436 and / or comprising the amino acid sequence of SEQ ID NO: 437;

[0142] Or wherein said antigen-binding peptide is a peptide, preferably an antibody, comprising an amino acid sequence having at least 90% identity, preferably at least 95% identity, more preferably at least 98% identity, and even more preferably 99% identity with any of the sequences shown in i.-lii.

[0143] The corresponding sequences are also outlined in Table 5 and are shown in detail in the Sequence Listing and Figure 16 (HCDR1-3 sequences and LCDR1-3 sequences) and Figure 17 (VH-sequences and VL-sequences).

[0144] The term "comprising", when used herein in connection with the amino acid sequence of a SEQ ID NO:, generally means allowing the presence of additional residues adjacent to such a sequence, said additional residues not being listed in the corresponding SEQ ID NO:. However, the term "comprising" also means including the possibility that such a sequence does not include any additional residues (not listed in the corresponding SEQ ID NO:), in which case such a term "comprising" is used in the sense of "consisting of" and should be understood as "consisting of". As an example, a region "comprising" the amino acid sequence of SEQ ID NO: xyz includes the sequence listed in SEQ ID NO: xyz, but may also include additional adjacent residues not listed in SEQ ID NO: xyz; however, such a term also includes the possibility that the region "consists only of the amino acid sequence of SEQ ID NO: xyz", in which case it means that additional adjacent residues are not covered and do not exist in said region.

[0145] In one embodiment, said antigen-binding peptide is an antibody selected from the antibodies shown in Table 5 below.

[0146] In one embodiment, said antigen-binding peptide is a human antibody, a humanized antibody or a chimeric human antibody.

[0147] In one embodiment, said antigen-binding peptide is a whole antibody, a substantially whole antibody, a Fab fragment, an F(ab')2 fragment or a single-chain Fv fragment.

[0148] In one embodiment, the antigen-binding peptide is capable of binding to a perilipin-1 fragment presented on adipocytes, and the binding of the antigen-binding peptide to the perilipin-1 fragment on the adipocytes activates the immune effector system to target and / or eliminate the adipocytes.

[0149] In one embodiment, the antigen-binding peptide comprises an Fc region, preferably an Fc region optimized by protein engineering, which has a higher binding affinity for effector cells compared to the binding affinity of an unoptimized Fc region.

[0150] In one embodiment, the antigen-binding peptide does not cross-react with any other perilipin (such as perilipin-2, perilipin-3, perilipin-4, or perilipin-5).

[0151] In another aspect, the antigen-binding peptide is an antigen-binding peptide for preventing or treating obesity.

[0152] The antigen-binding peptide is as defined above and elsewhere herein.

[0153] In another aspect, the present invention relates to a bispecific antigen-binding peptide, comprising:

[0154] (i) a first binding site that specifically binds to a perilipin-1 epitope having any one of SEQ ID NOs: 1-6, 330-333; and

[0155] (ii) a second binding site.

[0156] In one embodiment, the second binding site binds to a perilipin-1 epitope having any one of SEQ ID NOs: 1-6, 330-333, wherein the epitope is the same as or different from the epitope of the first binding site; the second binding site binds to a white adipocyte-specific surface marker (such as the neutral amino acid transporter ASC-1); or the second binding site binds to an immune cell-specific receptor molecule (such as a T cell-specific receptor molecule or a natural killer cell-specific receptor molecule).

[0157] The epitope is as defined in any of the above embodiments and elsewhere herein.

[0158] In another aspect, the bispecific antigen-binding peptide is a bispecific antigen-binding peptide for preventing or treating obesity.

[0159] In another aspect, the present invention further relates to a composition comprising the antigen-binding peptide of the present invention as defined herein and / or the bispecific antigen-binding peptide of the present invention as defined herein.

[0160] In one embodiment, the composition comprises more than one antigen-binding peptide of the invention as defined herein and / or more than one bispecific antigen-binding peptide of the invention as defined herein.

[0161] In one embodiment, when the composition comprises more than one antigen-binding peptide and / or more than one bispecific antigen-binding peptide, the more than one antigen-binding peptides are a group of peptides, each peptide in the group binds to a different perilipin-1 epitope, and the more than one bispecific antigen-binding peptides are a group of bispecific peptides, each bispecific peptide in the group binds to a different perilipin-1 epitope.

[0162] In one embodiment, the composition comprises at least two or at least three or at least four or at least five or at least six antigen-binding peptides of the invention as defined herein, each peptide binds to a different perilipin-1 epitope, and / or the composition comprises at least two or at least three or at least four or at least five or at least six bispecific antigen-binding peptides of the invention as defined herein, each bispecific antigen-binding peptide binds to a different perilipin-1 epitope.

[0163] In another aspect, the invention also relates to a composition comprising more than one antigen-binding peptide of the invention as defined herein and / or more than one antigen-binding peptide of the invention as defined herein, and the composition is used as a pharmaceutical composition for preventing or treating obesity.

[0164] In another aspect, the invention relates to a pharmaceutical composition comprising the antigen-binding peptide and / or the bispecific antigen-binding peptide, and the pharmaceutical composition is used for preventing or treating obesity.

[0165] The antigen-binding peptide and the bispecific antigen-binding peptide are as defined in any of the above embodiments and elsewhere herein.

[0166] In another aspect, the invention relates to an isolated nucleic acid encoding the antigen-binding peptide or encoding the bispecific antigen-binding peptide.

[0167] The antigen-binding peptide and the bispecific antigen-binding peptide are as defined in any of the above embodiments and elsewhere herein.

[0168] In another aspect, the invention relates to a recombinant cell comprising the nucleic acid, wherein the recombinant cell is preferably a recombinant autologous effector cell or a recombinant host cell.

[0169] The nucleic acid is as defined in any of the above embodiments and elsewhere herein.

[0170] In another aspect, the invention relates to a method of generating means for specifically targeting adipocytes presenting perilipin-1 fragments, the method comprising:

[0171] a) inoculating a non-human animal with an antigen comprising at least one perilipin-1 specific epitope selected from SEQ ID NO: 1-6, 330-333; and screening and generating antigen-binding peptides from the inoculated animal that specifically bind to the at least one perilipin-1 specific epitope, preferably harvesting cells expressing the antigen-binding peptide from the spleen of the non-human animal, preparing hybridoma cells from the cells, expressing the antigen-binding peptide, screening the antigen-binding peptide expressed by the hybridoma cells to identify an antigen-binding peptide that specifically binds to any one of SEQ ID NO: 1-6, 330-333, and isolating the antigen-binding peptide; or

[0172] b) providing and screening a recombinant antigen-binding peptide library (such as a library of antibodies, scFv molecules, camel antibodies, anticalin proteins or DARPins) to identify an antigen-binding peptide that specifically binds to any one of SEQ ID NO: 1-6, 330-333, and isolating the antigen-binding peptide; or

[0173] c) providing and screening a pool of cells comprising cytotoxic T cells (such as by tetramer staining or Dextramer technology) to identify cytotoxic T cells specific for any one of SEQ ID NO; 1-6, 330-333, and isolating the cytotoxic T cells; or

[0174] d) providing a blood sample from a patient and obtaining T cells from the blood sample, genetically modifying the T cells by introducing a nucleic acid as defined above and elsewhere herein, and obtaining T cells expressing a chimeric antigen receptor; or

[0175] e) providing and screening a pool of T cell receptors to identify T cell receptors specific for any one of SEQ ID NO: 1-6, 330-333, and isolating the T cell receptors.

[0176] In one embodiment, the means targets perilipin-1 and is selected from antigen-binding peptides and cytotoxic T cells.

[0177] The antigen-binding peptide and the epitope are as defined in any of the above embodiments and elsewhere herein.

[0178] In another aspect, the present invention also relates to the use of an antigen-binding peptide or a bispecific antigen-binding peptide in the preparation of a pharmaceutical composition for treating or preventing obesity.

[0179] The antigen-binding peptide, the bispecific antigen-binding peptide and the pharmaceutical composition are as defined above and elsewhere herein.

[0180] In another aspect, the present invention also relates to the use of an antigen-binding peptide, a bispecific antigen-binding peptide or a specific cytotoxic T cell in the preparation of a preparation, preferably a pharmaceutical preparation, for treating or preventing obesity.

[0181] The antigen-binding peptide, the bispecific antigen-binding peptide and the specific cytotoxic T cell are as defined above and elsewhere herein.

[0182] In another aspect, the present invention also relates to a method for preventing or treating obesity, the method comprising administering to a patient in need thereof an antigen-binding peptide, a bispecific antigen-binding peptide and / or a cytotoxic T cell that specifically binds to any one of the perilipin-1 epitopes having SEQ ID Nos. 1-6, 330, 333.

[0183] In one embodiment, the patient is a human.

[0184] The antigen-binding peptide, the bispecific antigen-binding peptide and the cytotoxic T cell are as defined above and elsewhere herein.

[0185] In another aspect, the present invention relates to the use of at least one perilipin-1 epitope having any one of SEQ ID NOs. 1-6, 330-333 for identifying an antigen-binding peptide, a bispecific antigen-binding peptide, and / or a cytotoxic T cell specific for adipocytes and / or useful in a method for treating or preventing obesity.

[0186] The antigen-binding peptide, the bispecific antigen-binding peptide and the cytotoxic T cell are as defined above and elsewhere herein. Detailed Description

[0187] As used herein, the term "antigen-binding peptide" refers to a peptide that specifically binds an antigen, preferably a peptide that binds a perilipin-1 epitope selected from any of SEQ ID NOs; 1-6. In one embodiment, the perilipin-1 epitope is selected from any of SEQ ID NOs. 1-6, 330-333. In one embodiment, the antigen-binding molecule is based on an immunoglobulin (such as a polyclonal or monoclonal antibody), or on a protein scaffold structure with antigen-binding ability (such as an anti-carrier protein, Affilin, Affimer, Affitin, Alphabody, nanobody or DARPin). In one embodiment, the antigen-binding peptide refers to an antibody or an antibody fragment. In one embodiment, when referring to an antibody or an antibody fragment, it refers to an antigen-binding peptide. There are several classes of antibodies, particularly human antibodies (such as IgA, IgG, IgM, IgD and IgE), and subtypes (such as IgG1, IgG2, IgG3 and IgG4). Antibodies are proteins mainly produced by plasma cells of the immune system to neutralize pathogens. Antibodies are grouped into classes also known as isotypes, as determined genetically by the constant region. Human constant light chains are divided into kappa (Cκ) and lambda (Cλ) light chains. Human heavy chains are divided into μ, δ, γ, α or ε, and the isotypes of antibodies are defined as IgM, IgD, IgG, IgA and IgE respectively. The IgG class is most commonly used for therapeutic purposes. As used herein, "IgG" refers to a polypeptide belonging to the antibody class substantially encoded by the recognized immunoglobulin gamma gene. In humans, this class includes IgG1, IgG2, IgG3 and IgG4 subtypes. In mice, this class includes IgG1, IgG2a, IgG2b and IgG3 subtypes. IgA has several subtypes, including but not limited to IgA1 and IgA2. Thus, as used herein, "isotype" refers to any class or subtype of immunoglobulin defined by the chemical and antigenic characteristics of its constant region. The known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD and IgE. IgG, as a hybrid composition of natural human IgG isotypes, can also be used in the present invention. Effector functions (such as ADCC, ADCP, CDC and serum half-life) vary significantly between different classes of antibodies, including for example human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgD, IgE and IgM. In one embodiment, the antigen-binding peptide may comprise domains of any of the above antibody classes, subtypes and / or chains. In one embodiment, the amino acid sequence of the antigen-binding peptide can be modified by protein engineering, for example to include a constant region from another immunoglobulin class that mediates improved effector function properties. Such engineered hybrid IgG compositions can provide improved effector function properties, including improved ADCC, phagocytosis, CDC and serum half-life.

[0188] According to the present invention, the antigen-binding peptide can relate to, for example, human antibodies, human chimeric antibodies, humanized antibodies, and antibody fragments. Antibodies recognize antigens through the variable regions of the Fab fragments containing complementarity-determining regions. The complementarity-determining regions specifically target epitopes on the antigen. In one embodiment, the antigen-binding peptide of the present invention binds to any one of the epitopes having SEQ ID NOs. 1-6, 330-333 on perilipin-1. In one embodiment, the binding of the antigen-binding peptide to a fragment of perilipin-1 presented on the cell surface of adipocytes results in the activation of the immune effector system to eliminate the adipocytes. Furthermore, as used herein, the term "antigen-binding peptide" relates to a peptide that specifically binds to a target antigen, such as one or more epitopes presented by or present on the target antigen. The antigen that binds to the antigen-binding peptide of the present invention is perilipin-1, or a bispecific molecule of perilipin-1 and an optional other antigen, such as an antigen on an effector cell (such as an antigen on a cytotoxic T cell, or an antigen other than a fragment of perilipin-1 presented on adipocytes, or an antigen presented by any component of adipose tissue). In one embodiment, the bispecific molecule comprises a first binding site that binds to one of the perilipin-1 epitopes having any one of SEQ ID NOs. 1-6, 330-333, and a second binding site that targets the same perilipin-1 epitope as the first binding site or a perilipin-1 epitope different from the epitope of the first binding site and having any one of SEQ ID NO: 1-6, 330-333. In one embodiment, the bispecific molecule comprises a first binding site that binds to one of the perilipin-1 epitopes having any one of SEQ ID NO: 1-6, 330-333, and a second binding site that targets an antigen different from perilipin-1.

[0189] In one embodiment, the antigen-binding peptide is a TCR-derived antigen-binding peptide and relates to a T cell receptor specific for any one of SEQ ID NOs: 1-6, 330-333, or a fragment of a T cell receptor specific for any one of SEQ ID NOs: 1-6, 330-333. In one embodiment, the T cell receptor can be a soluble T cell receptor or can be expressed on the surface of a genetically modified cell (preferably a T cell). In one embodiment, the TCR-derived antigen-binding peptide is used for adoptive T cell receptor transfer. In one embodiment, the antigen-binding peptide relates to a peptide expressed on the surface of a genetically modified cell (especially a T cell or an NK cell), wherein the genetically modified cell is genetically modified to express the antigen-binding peptide, thereby generating CAR-T cells or CAR-NK cells, respectively.

[0190] According to the present invention, the antigen-binding peptide may also relate to fragments of antibodies, such as substantially intact antibodies, Fab fragments, F(ab')2 fragments, diabodies, single-chain Fv fragments, tetravalent antibodies, trivalent antibodies, disulfide-stabilized Fv (dsFv), or heavy-chain VHH fragments from camels. However, other forms of antigen-binding peptides are also contemplated by the present invention. For example, the antigen-binding peptide may be another (non-antibody) receptor protein derived from a small and robust non-immunoglobulin scaffold, such as those receptor proteins equipped with binding functions by using methods of combinatorial protein design. Such non-antibody antigen-binding peptides may be, for example, affimer molecules, Affilins, Affimers, Affitins, Alphabodies, anticalins, nanobodies, or DARPins. The antigen-binding peptide may also relate to other antibody-mimicking molecules, such as dual-affinity retargeting antibodies (DARTs). In one embodiment, the antigen-binding peptide preferably relates to an antibody or an antibody fragment. In one embodiment, the antigen-binding peptide may relate to any antibody-mimicking molecule that mimics the binding properties of an antibody to an antigen but is structurally different from a naturally occurring antibody.

[0191] In one embodiment, the antigen-binding peptide may be optimized by protein engineering methods known to those skilled in the art, such as directed evolution, phage display, or ribosome display, to have improved properties, such as higher binding affinity and longer serum half-life compared to the unoptimized antigen-binding peptide. In one embodiment, certain effector functions may be induced by protein engineering methods known to those skilled in the art, such as by modifying the antigen-binding peptide by including an Fc region to be targeted by effector cells. In one embodiment, the optimized antigen-binding peptide may be engineered by specific amino acid exchanges in the amino acid sequence of the Fc region to increase the response of the effector system to the Fc region. In one embodiment, the optimized antigen-binding peptide may be optimized, for example, by modifying the CH3 region of the IgG domain to have an improved serum half-life. In one embodiment, the antigen-binding peptide may be modified by protein engineering methods known to those skilled in the art to improve the ability to induce certain effector functions, such as a stronger effector response of the complement system or cytotoxic T cells when the optimized antigen-binding peptide that binds to an epitope having any one of SEQ ID NOs: 1-6, 330-333 (presented on or present on the surface of adipocytes) is recognized, compared to the unoptimized antigen-binding peptide that binds to an epitope having any one of SEQ ID NOs: 1-6, 330-333 (presented on or present on the surface of adipocytes). In one embodiment, the antigen-binding peptide is a bispecific antigen-binding peptide.

[0192] As used herein, the terms "complementary determining region", "CDR", and "hypervariable region" refer to one or more hypervariable regions or complementary determining regions (CDRs) found in the variable region of the light or heavy chain of an antibody. The CDRs in each chain are held in close proximity by framework regions and together with the CDRs from the other chain contribute to form the antigen-binding site. In one embodiment, the antigen-binding peptide comprises at least one CDR, preferably all CDRs, of an antibody that specifically binds to a perilipin-1 fragment, preferably specifically binds to a perilipin-1 epitope having any one of SEQ ID NO: 1-6, 330-333. In one embodiment, the antigen-binding peptide comprises a peptide scaffold and at least one CDR, preferably all CDRs, of an antibody that specifically binds to a perilipin-1 fragment, wherein the peptide scaffold can be an antibody fragment or any non-antibody peptide scaffold (such as anticalin, Affilin, Affimer, Affitin, Alphabody, nanobody or DARPin).

[0193] As used herein, the term "bispecific antigen-binding peptide" refers to an artificial protein that comprises a first binding site that specifically binds to a perilipin-1 epitope having any one of SEQ ID NO: 1-6, 330-333, and a second binding site. The bispecific antigen-binding peptide can bind two target structures simultaneously, such as binding two different types of antigens. In one embodiment, the bispecific antigen-binding peptide is immunoglobulin-based. In one embodiment, the bispecific antigen-binding peptide comprises two different immunoglobulin-based binding fragments that have binding specificity for an antigen, and the two fragments are linked by a linker fragment (such as a linker peptide sequence and / or an antibody scaffold structure). In one embodiment, the binding fragments of the bispecific antigen-binding peptide can have specificity for different antigens, or for different epitopes on the same antigen, or for the same epitope on the same antigen. In one embodiment, the bispecific antigen-binding peptide of the present invention binds a first perilipin-1 epitope and a second but different non-overlapping perilipin-1 epitope. In one embodiment, the bispecific antigen-binding peptide of the present invention binds a perilipin-1 epitope and a different antigen. In one embodiment, the different antigen is a surface marker of an effector cell (such as a T cell or a natural killer cell). In one embodiment, the different antigen can also be an antigen presented on an adipocyte, rather than a perilipin-1 fragment, such as the neutral amino acid transporter ASC-1. In one embodiment, the different antigen can also be an antigen presented by any component of adipose tissue other than perilipin-1. In one embodiment, the bispecific antigen-binding peptide is a fusion protein that comprises a TCR-derived antigen-binding peptide. In one embodiment, the bispecific antigen-binding peptide comprises a TCR-derived antigen-binding peptide as the first binding site and a second binding site derived from a molecule selected from the group consisting of antibody fragments, anticalins, DARPins, aptamers, affimer molecules, Affilins, Affimers, Affitins, Alphabodies, and nanobodies. In one embodiment, the second binding site specifically binds to a receptor on an immune cell (such as a T cell or a natural killer cell), preferably a receptor capable of activating the immune cell or stimulating an immune response of the immune cell, wherein the immune response is preferably a cytotoxic immune response. In one embodiment, the receptor is preferably a receptor molecule, such as CD3, CD3δ / ε, CD3γ / ε, TCR, TCRα, TCRβ, CD2, CD5, CD28, OX40, 4-1BB, CD16, Ly49, NKp30 (CD337), NKp44 (CD336), NKp46 (NCR1), or CD3ζ (CD247).In one embodiment, the second binding site of the bispecific antigen-binding peptide specifically binds to a second perilipin-1 epitope having any one of SEQ ID NOs: 1-6, 330-333, and the second perilipin-1 epitope is different from and non-overlapping with the perilipin-1 epitope of the first binding site.

[0194] The invention also relates to a composition of one or several antigen-binding peptides and / or bispecific antigen-binding peptides according to the invention, and to the use of such compositions. For example, such a composition may be a composition comprising an antigen-binding peptide (e.g., an antibody) according to the invention and / or a bispecific antigen-binding peptide according to the invention. As another example, such a composition may be a composition comprising a plurality of different antigen-binding peptides (e.g., antibodies) according to the invention and / or a plurality of different bispecific antigen-binding peptides according to the invention. Such a composition of a plurality of different antigen-binding peptides (e.g., antibodies and / or different bispecific antigen-binding peptides) according to the invention is sometimes also referred to herein as a "pool" of different antigen-binding peptides (e.g., antibodies), and / or a "pool" of different bispecific antigen-binding peptides. Generally, in such a "pool", each different antigen-binding peptide (e.g., antibody) and / or each different bispecific antigen-binding peptide binds to a different perilipin-1 epitope as defined herein. For example, such a pool may be a pool of different antibodies, each different antibody binding to a different perilipin-1 epitope as defined herein. The perilipin-1 epitope as defined herein is preferably an epitope having an amino acid sequence selected from SEQ ID NOs: 1-6, 330-333.

[0195] As used herein, the term "autoantibody" refers to an antibody produced by a patient's immune system and directed against one or more proteins in the patient's own proteins. Many autoimmune diseases are caused by such autoantibodies. In one embodiment, anti-perilipin-1 autoantibodies are involved in acquired generalized lipodystrophy. In one embodiment, the anti-perilipin-1 autoantibodies trigger complement-mediated adipocyte destruction in acquired generalized lipodystrophy.

[0196] As used herein, the term "lipodystrophy" refers to a medical condition in which the body is unable to produce and maintain healthy adipose tissue. There are different types of lipodystrophy, such as congenital lipodystrophy syndrome and acquired lipodystrophy syndrome. The term "lipoatrophy" generally describes the (nearly) complete loss of adipose tissue from a region of the body or from the entire body. In one embodiment, lipodystrophy is used synonymously with lipoatrophy. In one embodiment, lipodystrophy refers to acquired generalized lipoatrophy (AGL). In one embodiment, the present invention discloses anti-perilipin-1 autoantibodies involved in lipometabolic disorders.

[0197] As used herein, the term "perilipin-1" is also referred to as lipid droplet-associated protein and refers to a protein associated with the surface of lipid droplets. Perilipin-1 belongs to the perilipin family, which is a family of proteins associated with the surface of lipid droplets. Perilipin-1 expression is elevated in obese individuals. Perilipin-1 protects lipid droplets from lipases involved in lipolysis. In humans, there are three perilipin-1 isoforms, namely perilipin-A, perilipin-B, and perilipin-C. The human amino acid sequence of perilipin-1 is identical to SEQ ID NO:7. In one embodiment, the term "perilipin-1" refers to the full-length protein of perilipin-1 and / or its fragments.

[0198] As used herein, the term "epitope" refers to the part of an antigen that is recognized by the immune system, particularly the part recognized by an antibody, B cell, or T cell. In one embodiment, epitope is used synonymously with antigenic determinant. The part of an antibody that binds to the epitope is the paratope. An epitope can be a conformational epitope or a linear epitope, depending on the structure and interaction with the paratope. In one embodiment, the antigen perilipin-1 contains six epitopes, wherein the epitopes have any of the sequences disclosed in SEQ ID NOs. 1-6, 330-333. The antibody or antigen-binding fragment according to the present invention can bind to one or more of SEQ ID NOs. 1-6, 330-333. In one embodiment, the antibody or antigen-binding fragment according to the present invention can also bind to a sequence having at least 85% identity to any of SEQ ID NOs. 1-6, 330-333.

[0199] As used herein, the term "antigen" refers to a molecule capable of inducing an immune response in an organism. An antigen can be targeted by an antibody. The antigenic determinant of an antigen is a unique surface feature, i.e., an epitope. Most antigens can be bound by multiple antibodies, each of which is typically specific for one of the epitopes of the antigen. An autoantigen is a normal protein of an organism that is recognized by the immune system of the organism suffering from a particular autoimmune disease. In one embodiment, the antigen refers to perilipin-1 protein and / or a fragment thereof. In one embodiment, the antigen, particularly a perilipin-1 fragment, is presented by MHC molecules on the surface of adipocytes. In one embodiment, the MHC molecule is an MHC-I molecule or an MHC-II molecule.

[0200] As used herein, the term "targeting" refers to the ability of a molecular structure, such as an antibody, an antigen-binding peptide, or a surface molecule of a cytotoxic T cell, to bind to a certain structure (such as an antigen, particularly an epitope) through specific interactions. In one embodiment, a perilipin-1 fragment on the surface of an adipocyte is targeted by an antigen-binding peptide, which results in the activation of an effector system, which in turn leads to the elimination of the adipocyte (e.g., via a caspase cascade). In one embodiment, a perilipin-1 fragment on the surface of an adipocyte is targeted by a cytotoxic T cell, which specifically binds to the perilipin-1, preferably leading to the cell death of the adipocyte. In one embodiment, the terms "targeting" and "recognizing" can be used interchangeably. In one embodiment, the antigen-binding peptide of the present invention targets the perilipin-1 protein and / or the perilipin-1 fragment, preferably targeting the perilipin-1 protein and / or the perilipin-1 fragment via an epitope having any one of SEQ ID NOs. 1-6, 330-333. In one embodiment, the antigen-binding peptide of the present invention targets a perilipin-1 fragment presented by MHC on the cell surface, or due to another mechanism, such a perilipin-1 fragment can be present on or presented on the cell surface. In one embodiment, the antigen-binding peptide targets at least one perilipin-1 epitope among the perilipin-1 epitopes having any one of SEQ ID NOs 1-6, 330-333. In one embodiment, the antigen-binding peptide is used to target a perilipin-1 fragment presented on adipocytes, preferably leading to the elimination of the adipocytes through an effector / elimination mechanism. In one embodiment, if the antigen-binding peptide binds to more than two of SEQ ID NO: 1-6 and SEQ ID NO: 330-333, the antigen-binding peptide preferably binds to any one of the following double or triple combinations a)-s):

[0201] a) SEQ ID NO.s 1 and 2; b) SEQ ID NO.s 1 and 5; c) SEQ ID NO.s 1 and 6; d) SEQ ID NO.s 2 and 5; e) SEQ ID NO.s 2 and 6; f) SEQ ID NO.s 5 and 6; g) SEQ ID NO.s 1, 2 and 5; h) SEQ ID NO.s 1, 2 and 6; i) SEQ ID NO.s 2, 5 and 6; k) SEQ ID NO.s 330 and 331; 1) SEQ ID NO.s 330 and 332; m) SEQ ID NO.s 330 and 333; n) SEQ ID NO.s 331 and 332; o) SEQ ID NO.s 331 and 333; p) SEQ ID NO.s 332 and 333; q) SEQ ID NO.s 330, 331 and 332; r) SEQ ID NO.s 330, 331 and 333; and s) SEQ ID NO.s 331, 332 and 333.

[0202] Alternatively, the present invention also contemplates that binding to more than one perilipin-1 epitope can be achieved by providing a composition (or "pool") of several different antigen-binding peptides of the invention as defined herein, each of the antigen-binding peptides binding a single perilipin-1 epitope that is different from the perilipin-1 epitope bound by other antigen-binding peptides in such composition (or "pool"). Thus, in one embodiment, such a composition can, for example, comprise two or three antigen-binding peptides that preferably bind any one of the aforementioned dual or triple combinations a)-s).

[0203] As used herein, the term "elimination" involves, for example, targeting a target cell and inducing cell destruction by means of the complement cascade, or by recruitment of NK cells, or by attack from cytotoxic T cells, and preferably also includes degradation and / or removal of the resulting cell debris. In one embodiment, the antigen-binding peptide of the present invention triggers the elimination of adipocytes by an effector mechanism. In one embodiment, the target adipocytes presenting perilipin-1 fragments on their surface are eliminated by inducing apoptosis via cytotoxic T cells or by lysing the cells via the complement cascade. In one embodiment, the term "elimination" may refer to damaging cells, destroying cells, degrading cells, and / or phagocytosing cells. In one embodiment, eliminating a cell means damaging the cell in a manner sufficient to terminate its viability and / or sufficient to terminate its ability to maintain its cellular functions. In many embodiments, elimination preferably involves complete removal of adipocytes. In many embodiments, "elimination" preferably involves the destruction and complete degradation of adipocytes by phagocytosis of the adipocytes, preferably without leaving extracellular cell debris. In one embodiment, an antigen-binding peptide is used to target perilipin-1 presented on adipocytes to eliminate the adipocytes. In one embodiment, the elimination of adipocytes can be triggered by one effector mechanism, by several effector mechanisms simultaneously, or by a cascade of effector mechanisms.

[0204] As used herein, the term "effector mechanism" involves mechanisms that participate in and / or result in the elimination of target cells. Effector mechanisms as used herein can involve various mechanisms of action that participate in the destruction of target cells, such as activating death pathways in the target cells, blocking essential growth factor / growth factor receptor interactions, inducing antibody-dependent cell cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) responses, and / or antibody-dependent cell phagocytosis (ADCP). In one embodiment, the effector mechanism is an immune effector mechanism, which is the mechanism by which the immune system eradicates cells such as infected cells. In one embodiment, the "effector mechanism" can be used interchangeably with the "effector system". In one embodiment, the term effector mechanism can refer to an individual effector mechanism that participates in the elimination of adipocytes, or to a group of several effector mechanisms that participate simultaneously or as part of a cascade of effector mechanisms in the elimination of adipocytes.

[0205] In one embodiment, the interaction of the antigen-binding peptide with complement triggers a complement-dependent cytotoxicity (CDC) response. In one embodiment, the binding of the antigen-binding peptide to perilipin-1 fragments presented on the surface of adipocytes mediates apoptosis of the adipocytes. In one embodiment, the antigen-binding peptide comprises an Fc (fragment crystallizable)-derived region that preferably mediates effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cell phagocytosis (ADCP), through interaction with Fc receptors expressed on effector cells and / or interaction with components of the complement system, such as complement component 1q (C1q). In one embodiment, the antigen-binding peptide comprises an Fc region that contributes to the long half-life of the antigen-binding peptide by binding to the salvage receptor FcRn. In one embodiment, the glycosylation of the antigen-binding peptide can alter the intensity of the effector functions mediated by the antigen-binding peptide. In one embodiment, effector cells, such as NK cells, monocytes, macrophages, and granulocytes, recognize the antigen-binding peptide of the present invention bound to a target cell (preferably an adipocyte), such recognition occurring, for example, via the FcγR receptor of the effector cell and the Fc domain of the antigen-binding peptide, and such recognition triggers the release by the effector cells of cytoplasmic perforin, granulysin, and granzymes that induce apoptosis and / or lysis of the target cell. In one embodiment, the effector mechanism leading to adipocyte destruction can also comprise a cytotoxic drug, toxin, or radionuclide that is delivered to the adipocyte by the antigen-binding peptide of the present invention, such as by conjugating the cytotoxic drug, toxin, or radionuclide to the antigen-binding peptide, or by delivering the cytotoxic drug, toxin, or radionuclide to the adipocyte using liposomes labeled with the antigen-binding peptide.

[0206] In one embodiment, the effector mechanism may also involve a chimeric antigen receptor (CAR), which is a receptor protein that has been engineered to confer on T cells the ability to target a specific protein. In particular, T cells are harvested from a patient and genetically altered to include a chimeric antigen receptor comprising the antigen-binding peptide of the present invention, for example, by transforming the T cells with a plasmid / virus containing the genetic information of a fusion protein comprising an antigen-binding peptide such as a TCR-derived antigen-binding peptide, as well as a transmembrane domain and a cytoplasmic effector domain, and then administering the genetically altered T cells as CAR-T cells to the patient to attack adipocytes. In one embodiment, the CAR-T cells may be derived from T cells of the patient's own blood (autologous cells) or from T cells of another healthy individual (allogeneic cells). In one embodiment, the CAR comprises an antigen-binding peptide specific for any one of SEQ ID NOs. 1-6, 330-333 as an extracellular domain, as well as a transmembrane domain and an intracellular domain. In one embodiment, the antigen-binding peptide specific for any one of SEQ ID NOs. 1-6, 330-333 may be a T cell receptor or a domain of a T cell receptor. In one embodiment, the effector mechanism may involve T cells genetically altered to be specific for any one of SEQ ID NOs. 1-6, 330-333 and / or T cells that are naturally specific for any one of SEQ ID NOs. 1-6, 330-333, selected from a pool of T cells obtained from a donor and expanded in vitro, wherein the donor may be autologous or allogeneic.

[0207] As used herein, the term "effector cell" refers to a cell that participates in an effector system and / or effector mechanism that results in the destruction and / or elimination of a target cell, preferably an immune cell. In one embodiment, the effector cell may be a monocyte, macrophage, neutrophil, NK cell, NKT cell, or cytotoxic T cell. In one embodiment, the effector cell recognizes and / or binds to the antigen-binding peptide of the present invention that binds to the perilipin-1 fragment presented on adipocytes, recognizes and / or binds to the perilipin-1 fragment presented on adipocytes, or recognizes and / or binds to a complex thereof. In one embodiment, the recognition and / or binding induces an effector mechanism, thereby resulting in the elimination / destruction of the adipocytes. In one embodiment, an effector cell such as a T cell recognizes an adipocyte target cell and induces cell death of the target cell. In one embodiment, an effector cell (such as an NK cell, monocyte, macrophage, or granulocyte) recognizes the antigen-binding peptide of the present invention that binds to an adipocyte, and this recognition triggers the induction of apoptosis or lysis of the adipocyte and / or phagocytosis of the adipocyte.

[0208] As used herein, the term "adipocyte" refers to adipocytes that specifically store fat. Adipose tissue is mainly composed of adipocytes. There are different types of adipose tissue, namely white fat, brown fat, beige fat, and bone marrow fat, and accordingly there are also different types of adipocytes. White adipocytes are monovacuolar cells containing a large lipid droplet surrounded by a cytoplasmic layer. Brown adipocytes are plurivacuolar and usually polygonal in shape. Beige fat contains white adipocytes and brown adipocytes, making beige fat metabolically more desirable than white fat. There are also adipocytes in bone marrow adipose tissue, which also seems to play a role in obesity. In one embodiment, the terms "adipocytes presenting perilipin-1" and "adipocytes presenting perilipin-1 fragments" are used interchangeably. In one embodiment, adipocytes preferably present fragments of perilipin-1 on their surface. In one embodiment, the fragment of perilipin-1 presented on the surface of adipocytes preferably comprises any one of SEQ ID NOs. 1-6, 330-333.

[0209] As used herein, the term "direct elimination mechanism" refers to the process and / or ability of the immune effector system to directly destroy target cells and remove their components. In one embodiment, the binding of an antigen-binding peptide to perilipin-1 or its fragment mediated by an Fc receptor activates macrophages to destroy target cells and remove their components. In one embodiment, the direct elimination mechanism involves neutrophils (neutrophilic polymorphonuclear leukocytes) through the binding of an antibody or antigen-binding fragment mediated by an Fc receptor to perilipin-1 or its fragment. In one embodiment, the direct elimination mechanism preferably includes the binding of macrophages and / or neutrophils to an antigen-binding peptide that binds to a perilipin-1 fragment on the surface of adipocytes, wherein the binding results in the phagocytosis of the adipocytes, and wherein the binding is preferably mediated by an Fc receptor.

[0210] As used herein, the term "indirect elimination mechanism" relates to the process and / or ability of the immune effector system to target a target cell and to another system that disrupts the target cell and / or removes cell remnants. In one embodiment, the indirect elimination mechanism involves the binding of an antigen-binding peptide to a target structure on the surface of an adipocyte, such as perilipin-1 or a fragment thereof. In one embodiment, the binding triggers the disruption of the adipocyte through the activation of the complement cascade. In one embodiment, the mechanism is complement-dependent cytotoxicity (CDC). In one embodiment, the indirect elimination mechanism involves antibody-dependent cell-mediated cytotoxicity (ADCC), which involves effector cells of the immune system, such as natural killer cells, to lyse the target cell. In one embodiment, the indirect elimination involves antibody-dependent cell phagocytosis (ADCP), which involves the phagocytosis of adipocytes by effector cells of the immune system, such as macrophages. In one embodiment, the indirect elimination mechanism involves cytotoxic T cell-mediated cytotoxicity, which involves the lysis of adipocytes by effector cells that directly bind to a perilipin-1 fragment presented via MHC on the adipocyte. Then, the disruption of the adipocyte triggers the activation of another system, resulting in the elimination of the debris of the disrupted adipocyte, such as by phagocytosis. In one embodiment, the indirect elimination mechanism involves the phagocytosis of target cell remnants by macrophages or neutrophils (polymorphonuclear neutrophils). In one embodiment, the means for specifically targeting and / or eliminating adipocytes can have both direct elimination ability and indirect elimination ability. In one embodiment, macrophages and neutrophils are both direct elimination means, such as by Fc receptor-dependent binding to target adipocytes and their phagocytosis, while macrophages and neutrophils are also indirect elimination means, such as by phagocytosing the debris of disrupted adipocytes that have been targeted by different elimination means, such as complement-mediated opsonization. In one embodiment, the direct elimination mechanism and the indirect elimination mechanism can occur simultaneously and / or their scopes can overlap. In one embodiment, the term "effector mechanism" can refer to both the indirect elimination mechanism and the direct elimination mechanism simultaneously. In one embodiment, the terms "effector mechanism" and "elimination mechanism" can be used synonymously.

[0211] As used herein, the term "effector system" or "immune effector system" refers to any system involved in the immune system that can potentially contribute to an immune response. The immune effector system can, for example, involve the complement system, T cells (such as cytotoxic T cells or regulatory T cells), natural killer cells, B cells, plasma cells, or macrophages. In one embodiment, the effector system involves the complement system, macrophages, neutrophils, NK cells, NKT cells, and / or cytotoxic T cells. In one embodiment, the effector system is triggered by the binding of an antigen-binding peptide to perilipin-1 presented on adipocytes, and said triggering results in the elimination of the adipocytes.

[0212] As used herein, the term "endogenous effector system" refers to an endogenous immune effector system. The endogenous effector system can be, for example, the complement system, which can trigger target cell destruction upon activation, for example, by opsonization. The endogenous effector system can also involve endogenous cytotoxic T cells activated by a specific antigen. The endogenous effector system can also involve macrophages, or neutrophils such as polymorphonuclear neutrophils, or NK cells.

[0213] As used herein, the term "exogenous effector system" refers to an exogenous immune effector system. The exogenous effector system can be, for example, cytotoxic T cells that are expanded ex vivo and subsequently administered to a patient. Such ex vivo-expanded cytotoxic T cells can be from the patient or from a donor, or can be from a commercially available source. In one embodiment, the exogenous effector system can involve chimeric antigen receptor T cells (CAR-T cells), which are genetically modified T cells expressing a T cell receptor specific for any one of SEQ ID NOs. 1-6, 330-333. In one embodiment, the exogenous effector system can also involve an exogenous T cell receptor (TCR), wherein the exogenous TCR can be a soluble TCR or a TCR expressed by an effector cell such as a T cell, preferably a T cell transformed to express a TCR specific for any one of SEQ ID NO: 1-6, 330-333.

[0214] As used herein, the term "complement system" refers to a part of the innate immune system that enhances the ability of antibodies and phagocytes to clear damaged cells from an organism. More than thirty proteins are involved in the complement system. The complement system is capable of triggering different immune functions, such as phagocytosis of opsonized antigens, inflammation by attracting macrophages and neutrophils, and membrane attack. The classical complement pathway generally requires an antigen-antibody complex to activate. The complement system can involve the membrane attack complex, which forms a transmembrane channel, thereby causing osmotic lysis of the target cell. In addition, macrophages help clear complement-coated target cells.

[0215] As used herein, the term "cytotoxic T cell" refers to a T lymphocyte capable of killing cancer cells, infected cells, or otherwise damaged cells. T cells typically express a T cell receptor (TCR) that specifically recognizes an antigen. Such an antigen is typically presented on the cell surface via an MHC-I molecule. If the T cell receptor of a cytotoxic T cell is specific for the antigen, it will bind to the complex of the antigen and the MHC-I molecule and destroy the cell. The interaction of the T cell with the complex of the antigen and the MHC-I molecule of the target cell typically also involves a co-receptor, namely, CD8. In one embodiment, when the T cell binds to such a complex on the target cell, it releases any one of the cytotoxins perforin, granzyme, and granulysin. In one embodiment, granzyme enters the cytoplasm of the target cell through the action of perforin, and their serine protease function triggers a caspase cascade, resulting in apoptosis of the target cell. In one embodiment, apoptosis of the target cell can also be induced by cell surface interactions between the cytotoxic T cell and the target cell, such as through Fas-Fas ligand interactions.

[0216] As used herein, the term "means for specifically targeting adipocytes presenting perilipin-1 fragments" refers to any means capable of specifically targeting perilipin-1 fragments presented on the surface of adipocytes and capable of directly and / or indirectly triggering the elimination of said adipocytes. In one embodiment, the means for specifically targeting adipocytes presenting perilipin-1 fragments involves an antigen-binding peptide capable of recognizing the perilipin-1 fragment, preferably by epitope specificity having any one of SEQ ID NOs: 1-6, 330-333. In one embodiment, the means for specifically targeting adipocytes presenting perilipin-1 fragments includes an effector mechanism for triggering the elimination of said adipocytes and / or inducing such an effector mechanism. In one embodiment, the means for specifically targeting adipocytes presenting perilipin-1 fragments involves a cytotoxic T cell having a T cell receptor specific for perilipin-1, preferably specific for an epitope of perilipin-1 having any one of SEQ ID NOs: 1-6, 330-333. In one embodiment, the means for specifically targeting adipocytes presenting perilipin-1 fragments triggers an indirect elimination mechanism and / or a direct elimination mechanism. In one embodiment, the means for specifically targeting adipocytes presenting perilipin-1 fragments is preferably a means for specifically eliminating adipocytes presenting perilipin-1 fragments. In one embodiment, the means is capable of eliminating adipocytes presenting perilipin-1 and / or capable of inducing an effector mechanism for eliminating adipocytes presenting perilipin-1.

[0217] As used herein, the term "specific" or "specifically binds" refers to an antibody or immunoreceptor fragment that can specifically interact with and / or bind to a specific antigen or a group of specific antigens, but essentially does not bind to other antigens. This binding can be exemplified by the specificity of the lock and key principle.

[0218] As used herein, the term "nucleic acid" refers to a nucleotide sequence, such as ribonucleic acid or deoxyribonucleic acid. In one embodiment, the nucleic acid encodes an antigen-binding peptide of other embodiments of the present invention. In one embodiment, the nucleic acid encodes a sequence that is at least 50%, preferably at least 85% identical to the nucleic acid sequence encoding the antigen-binding peptide of other embodiments of the present invention. In one embodiment, due to the redundancy of the genetic code, the nucleic acid that is at least 50%, preferably at least 85% identical to the nucleic acid sequence encoding the antigen-binding peptide produces the same peptide product as the 100% identical sequence.

[0219] As used herein, the term "non-human animal" refers to a non-human animal, preferably a mammal.

[0220] As used herein, the term "immunization" refers to the administration of an antigen that preferably has at least one epitope having a sequence according to any one of SEQ ID NOs: 1-6, 330-333 for immunization and generating antibodies or antigen-binding fragments specific for the antigen.

[0221] As used herein, the term "screening" refers to analyzing the binding specificity of certain candidates of molecules or cells to a certain antigen (preferably perilipin-1). The purpose of this screening is to identify molecules, such as antigen-binding peptides, or cells such as cytotoxic T cells, that specifically bind to a certain antigen (preferably perilipin-1) with high affinity (preferably with an affinity of at least 10 -9 M), or with respect to TCR-derived antigen-binding fragments, preferably with an affinity of at least 10 -9 M. In one embodiment, the best candidates identified by screening are subsequently amplified, for example, by cell culture amplification, preferably in vitro amplification.

[0222] As used herein, the term "host cell" refers to a cell that can be used to produce the antigen-binding peptides of the present invention. In one embodiment, the host cell allows the production of antibodies or antigen-binding fragments, such as yeast cells or Chinese hamster ovary (CHO) cells. In one embodiment, the host cell is transformed to contain a nucleic acid encoding the antigen-binding peptide of the present invention, and the transformed host cell is referred to as a recombinant cell. In one embodiment, the host cell is an autologous or allogeneic effector cell, such as a T cell or an NK cell, which can be transformed into a CAR-T cell or a CAR-NK cell, respectively. In one embodiment, such a cell is a genetically modified cell that contains a nucleic acid encoding an antigen-binding peptide specific for perilipin-1.

[0223] As used herein, the term "obesity" refers to a medical condition in which excessive body fat accumulates in the body to an extent that may have a negative impact on the health of the body. In one embodiment, means for specifically eliminating adipocytes presenting perilipin-1 fragments, such as perilipin-1 fragment-specific antigen-binding peptides or perilipin-1-specific cytotoxic T cells, are used to target and / or eliminate adipocytes in a patient suffering from obesity.

[0224] As used herein, the term "binding assay" refers to an assay or analytical procedure for studying the binding of an antigen-binding peptide to an antigen. In one embodiment, a binding assay can refer to flow cytometry, tetramer staining, Western blotting, fluorescence analysis, surface plasmon resonance, or other binding assays known to those skilled in the art. In one embodiment, a binding assay (e.g., tetramer staining) can also refer to an assay for studying the binding of a cytotoxic T cell to an antigen, preferably the binding of the T cell receptor of the cytotoxic T cell to the antigen. In one embodiment, a binding assay can involve surface plasmon resonance measurements.

[0225] As used herein, the term "K D " refers to the dissociation constant, which is the reciprocal of the association constant. In one embodiment, the antigen-binding peptides of the present invention bind to the antigen with an affinity (K -4 ) of at least 10 D M. In one embodiment, the antigen-binding peptide is a peptide selected from antibodies, antibody-derived fragments, and non-antibody antigen-binding peptides (such as antigen-binding proteins or DARPins), and binds to the antigen with an affinity (K -7 ) of at least 10 -9 M, preferably at least 10 -11 M, more preferably at least 10 D )M. In one embodiment, the antigen-binding peptide is a TCR-derived antigen-binding peptide and binds to the antigen with an affinity (K -4 ) of at least 10D ) binds to an antigen and / or an MHC - antigen complex. In one embodiment, the term "at least 10 -4 M affinity (K D )" means that the K D value is 10 -4 M or less, such as 10 -5 M, 10 -6 M or 10 -7 M.

[0226] As used herein, the term "monoclonal antibody" or "mAB" refers to an antibody obtained from a substantially homogeneous population of antibodies based on their amino acid sequences. Monoclonal antibodies are typically highly specific. In addition, in contrast to polyclonal antibody preparations, which generally include different antibodies directed against different epitopes of an antigen, mAbs typically target a single epitope on an antigen. In addition to their specificity, mAbs are advantageous because mAbs can be synthesized by cell culture, such as by hybridoma cell culture or recombinant host cells that are not contaminated with other immunoglobulins. In one embodiment, an mAB refers to a chimeric, humanized or human antibody or antibody fragment. In one embodiment, a monoclonal antibody can be an optimized monoclonal antibody having an Fc region that has been engineered to have improved binding properties for targeting by effector cells. In one embodiment, the optimized monoclonal antibody can be engineered by specific amino acid exchanges in the amino acid sequence of the Fc region. In one embodiment, the optimized monoclonal antibody can also be optimized, for example, by modifying the CH3 region of IgG to have an improved serum half - life.

[0227] As used herein, the term "human antibody" refers to an antibody that contains only human sequences or fragments thereof. In one embodiment, human antibodies are produced by display techniques, such as by phage display or ribosome display.

[0228] As used herein, the term "humanized antibody" refers to an immunoglobulin chain or fragment thereof, such as a Fab fragment, Fab' fragment, F(ab′)2 fragment, Fv fragment, or other antigen - binding fragment of an antibody, that contains sequences from a non - human immunoglobulin. In one embodiment, a humanized antibody is a human antibody in which certain CDR residues are replaced with CDR residues from a non - human source having the desired specificity and affinity characteristics.

[0229] As used herein, the term "chimeric - human antibody" refers to an artificial antibody designed by genetic engineering or protein engineering by combining sequences from different species, such as mouse and human. In one embodiment, a human chimeric antibody is a hybrid protein consisting of the antigen - binding domain of a mouse antibody and the constant domain of a human antibody.

[0230] As used herein, the term "substantially intact antibody" refers to an antibody that is not fragmented, truncated or otherwise shortened and retains its ability to specifically bind an antigen.

[0231] As used herein, the term "cross-reactivity" refers to off-target binding to a structure that is not the target structure. In one embodiment, "cross-reactivity" refers to the binding of an antibody, antigen-binding fragment or cytotoxic T cell to a protein that is not perilipin-1 (such as perilipin-2, perilipin-3, perilipin-4 or perilipin-5).

[0232] As used herein, the term "(%) sequence identity" refers to the percentage of pairwise identical residues in a homology alignment of the sequence of a polypeptide / nucleic acid of the invention with the sequence being discussed.

[0233] As used herein, the term "patient" can refer to a human or an animal. A blood sample for obtaining T cells and / or antibodies can be an autologous sample or an allogeneic sample.

[0234] As used herein, the term "recombinant antigen-binding peptide library" refers to a pool of antigen-binding peptides generated by methods of protein engineering known to those skilled in the art. For example, such a pool of antigen-binding peptides can be generated and screened by phage display, yeast display, mRNA display, or ribosome display. The display library displays single-chain variable domain antigen-binding fragments such as scFvs or Fab fragments and contains encoding DNA or RNA. The genetic diversity of these libraries is typically generated by cloning libraries of immunoglobulin heavy and light chain variable gene segments from an initial or immunized individual, or by randomizing antigen-binding fragments using synthetic DNA, or by a combination of these methods, optionally in combination with error-prone PCR. In one embodiment, the antigen-binding peptide can be optimized to enhance the effector function and / or half-life of the antigen-binding peptide.

[0235] As used herein, the term "optimized" refers to enhanced properties of a peptide modified by protein engineering compared to the unmodified form of the peptide. In one embodiment, the antigen-binding peptide is optimized for the strength and / or type of effector function it elicits by an effector system, for example by designing the antigen-binding peptide to contain an Fc region recognized by the Fc receptor of macrophages, monocytes, neutrophils, NK cells or another effector cell. In one embodiment, the Fc region is genetically engineered to contain amino acid exchanges and / or altered glycosylation compared to the unmodified Fc region. In one embodiment, the serum half-life of the antigen-binding peptide is increased by designing the peptide to contain the CH3 region of an IgG domain that increases half-life, or by modifying the antigen-binding peptide with other half-life-increasing molecules. Sequence Listing <110> Elites Therapeutics, Inc. <120> Method for specifically eliminating adipocytes presenting perilipin-1 fragments <130> FSP1V212424JW <150> EP19156940.9 <151> 2019-02-13 <160> 439 <170> BiSSAP 1.3.6 <210> 1 <211> 10 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 1 Leu Thr Leu Leu Asp Gly Asp Leu Pro Glu 1 5 10 <210> 2 <211> 8 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 2 Glu Lys Ile Ala Ser Glu Leu Lys 1 5 <210> 3 <211> 10 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 3 Val Pro Ile Ala Ser Thr Ser Asp Lys Val 1 5 10 <210> 4 <211> 10 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 4 Pro Ala Pro Gly His Gln Gln Ala Gln Lys 1 5 10 <210> 5 <211> 12 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 5 Pro Ser Leu Leu Ser Arg Val Gly Ala Leu Thr Asn 1 5 10 <210> 6 <211> 8 <212> PRT <213> Homo sapiens <220> <223> Epitope <400> 6 Pro Trp Leu His Ser Leu Ala Ala 1 5 <210> 7 <211> 522 <212> PRT <213> Homo sapiens <220> <223> Human perilipin-1 full length <400> 7 Met Ala Val Asn Lys Gly Leu Thr Leu Leu Asp Gly Asp Leu Pro Glu 1 5 10 15 Gln Glu Asn Val Leu Gln Arg Val Leu Gln Leu Pro Val Val Ser Gly 20 25 30 Thr Cys Glu Cys Phe Gln Lys Thr Tyr Thr Ser Thr Lys Glu Ala His 35 40 45 Pro Leu Val Ala Ser Val Cys Asn Ala Tyr Glu Lys Gly Val Gln Ser 50 55 60 Ala Ser Ser Leu Ala Ala Trp Ser Met Glu Pro Val Val Arg Arg Leu 65 70 75 80 Ser Thr Gln Phe Thr Ala Ala Asn Glu Leu Ala Cys Arg Gly Leu Asp 85 90 95 His Leu Glu Glu Lys Ile Pro Ala Leu Gln Tyr Pro Pro Glu Lys Ile 100 105 110 Ala Ser Glu Leu Lys Asp Thr Ile Ser Thr Arg Leu Arg Ser Ala Arg 115 120 125 Asn Ser Ile Ser Val Pro Ile Ala Ser Thr Ser Asp Lys Val Leu Gly 130 135 140 Ala Ala Leu Ala Gly Cys Glu Leu Ala Trp Gly Val Ala Arg Asp Thr 145 150 155 160 Ala Glu Phe Ala Ala Asn Thr Arg Ala Gly Arg Leu Ala Ser Gly Gly 165 170 175 Ala Asp Leu Ala Leu Gly Ser Ile Glu Lys Val Val Glu Tyr Leu Leu 180 185 190 Pro Pro Asp Lys Glu Glu Ser Ala Pro Ala Pro Gly His Gln Gln Ala 195 200 205 Gln Lys Ser Pro Lys Ala Lys Pro Ser Leu Leu Ser Arg Val Gly Ala 210 215 220 Leu Thr Asn Thr Leu Ser Arg Tyr Thr Val Gln Thr Met Ala Arg Ala 225 230 235 240 Leu Glu Gln Gly His Thr Val Ala Met Trp Ile Pro Gly Val Val Pro 245 250 255 Leu Ser Ser Leu Ala Gln Trp Gly Ala Ser Val Ala Met Gln Ala Val 260 265 270 Ser Arg Arg Arg Ser Glu Val Arg Val Pro Trp Leu His Ser Leu Ala 275 280 285 Ala Ala Gln Glu Glu Asp His Glu Asp Gln Thr Asp Thr Glu Gly Glu 290 295 300 Asp Thr Glu Glu Glu Glu Glu Leu Glu Thr Glu Glu Asn Lys Phe Ser 305 310 315 320 Glu Val Ala Ala Leu Pro Gly Pro Arg Gly Leu Leu Gly Gly Val Ala 325 330 335 His Thr Leu Gln Lys Thr Leu Gln Thr Thr Ile Ser Ala Val Thr Trp 340 345 350 Ala Pro Ala Ala Val Leu Gly Met Ala Gly Arg Val Leu His Leu Thr 355 360 365 Pro Ala Pro Ala Val Ser Ser Thr Lys Gly Arg Ala Met Ser Leu Ser 370 375 380 Asp Ala Leu Lys Gly Val Thr Asp Asn Val Val Asp Thr Val Val His 385 390 395 400 Tyr Val Pro Leu Pro Arg Leu Ser Leu Met Glu Pro Glu Ser Glu Phe 405 410 415 Arg Asp Ile Asp Asn Pro Pro Ala Glu Val Glu Arg Arg Glu Ala Glu 420 425 430 Arg Arg Ala Ser Gly Ala Pro Ser Ala Gly Pro Glu Pro Ala Pro Arg 435 440 445 Leu Ala Gln Pro Arg Arg Ser Leu Arg Ser Ala Gln Ser Pro Gly Ala 450 455 460 Pro Pro Gly Pro Gly Leu Glu Asp Glu Val Ala Thr Pro Ala Ala Pro 465 470 475 480 Arg Pro Gly Phe Pro Ala Val Pro Arg Glu Lys Pro Lys Arg Arg Val 485 490 495 Ser Asp Ser Phe Phe Arg Pro Ser Val Met Glu Pro Ile Leu Gly Arg 500 505 510 Thr His Tyr Ser Gln Leu Arg Lys Lys Ser 515 520 <210> 8 <211> 8 <212> PRT <213> Homo sapiens <400> 8 Pro Glu Lys Glu Pro Pro Lys Pro 1 5 <210> 9 <211> 9 <212> PRT <213> Homo sapiens <400> 9 Pro Ile Leu Val Glu Arg Pro Glu Pro 1 5 <210> 10 <211> 8 <212> PRT <213> Homo sapiens <400> 10 Glu Lys Ile Ala Ser Glu Leu Lys 1 5 <210> 11 <211> 10 <212> PRT <213> Homo sapiens <400> 11 Val Pro Ile Ala Ser Thr Ser Asp Lys Val 1 5 10 <210> 12 <211> 10 <212> PRT <213> Homo sapiens <400> 12 Pro Ala Pro Gly His Gln Gln Ala Gln Lys 1 5 10 <210> 13 <211> 12 <212> PRT <213> Homo sapiens <400> 13 Pro Ser Leu Leu Ser Arg Val Gly Ala Leu Thr Asn 1 5 10 <210> 14 <211> 8 <212> PRT <213> Homo sapiens <400> 14 Pro Trp Leu His Ser Leu Ala Ala 1 5 <210> 15 <211> 10 <212> PRT <213> Homo sapiens <400> 15 Leu Thr Leu Leu Asp Gly Asp Leu Pro Glu 1 5 10 <210> 16 <211> 8 <212> PRT <213> Homo sapiens <400> 16 Pro Glu Lys Glu Pro Pro Lys Pro 1 5 <210> 17 <211> 9 <212> PRT <213> Homo sapiens <400> 17 Pro Ile Leu Val Glu Arg Pro Glu Pro 1 5 <210> 18 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 18 Ser Tyr Ala Met His 1 5 <210> 19 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 19 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 20 Ile Ala Ala Ala Gly Pro Phe Asp Tyr 1 5 <210> 21 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 21 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Asn 1 5 10 <210> 22 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 22 Tyr Asp Asp Leu Leu Pro Ser 1 5 <210> 23 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 23 Ala Ala Trp Asp Asp Ser Leu Asn Gly Val Val 1 5 10 <210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 24 Ser Tyr Ala Met Ser 1 5 <210> 25 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 25 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 26 Gly Phe Arg Arg Leu Phe Asp Pro 1 5 <210> 27 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 27 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 28 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 28 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 29 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 29 Ser Ser Tyr Thr Ser Ser Ser Thr His Val Val 1 5 10 <210> 30 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 30 Ser Tyr Ala Met His 1 5 <210> 31 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 31 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 32 <211> 11 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 32 Phe Ala Ser Ile Ala Ala Arg Pro Phe Asp Tyr 1 5 10 <210> 33 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 33 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <210> 34 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 34 Ser Asn Asn Gln Arg Pro Ser 1 5 <210> 35 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 35 Ala Ala Trp Asp Asp Ser Leu Asn Gly Arg Tyr Val 1 5 10 <210> 36 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 36 Ser Tyr Gly Ile Ser 1 5 <210> 37 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 37 Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <210> 38 <211> 7 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 38 Gly Gly Ser Ser Ser Asn Tyr 1 5 <210> 39 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 39 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 40 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 40 Glu Val Ser Asn Arg Pro Ser 1 5 <210> 41 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 41 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <210> 42 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 42 Ser Tyr Gly Met His 1 5 <210> 43 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 43 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 44 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 44 Asn Pro Ser Ser Gly Ala Asp Tyr 1 5 <210> 45 <211> 13 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 45 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr 1 5 10 <210> 46 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 46 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 47 <211> 12 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 47 Ala Ala Trp Asp Asp Ser Leu Ser Gly Ala Trp Val 1 5 10 <210> 48 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 48 Ser Tyr Ala Ile Ser 1 5 <210> 49 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 49 Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 50 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 50 Ser His Ser Ser Gly Trp Glu Trp 1 5 <210> 51 <211> 13 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 51 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr 1 5 10 <210> 52 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 52 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 53 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 53 Ala Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <210> 54 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 54 Ser Tyr Gly Ile Ser 1 5 <210> 55 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 55 Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <210> 56 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 56 Leu Tyr Cys Ser Gly Gly Ser Cys Tyr Ser Ala Leu Asp Pro 1 5 10 <210> 57 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 57 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 58 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 58 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 59 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 59 Gln Ser Tyr Asp Ser Ser Leu Arg Tyr Val Val 1 5 10 <210> 60 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 60 Asp Tyr Ala Met His 1 5 <210> 61 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 61 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 62 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 62 Glu Asp Gly Ser Tyr Ala Leu Asp Tyr 1 5 <210> 63 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 63 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 64 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 64 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 65 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 65 Gln Gln Ser Tyr Ser Thr Pro Pro Thr 1 5 <210> 66 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 66 Asp Tyr Ala Met His 1 5 <210> 67 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 67 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 68 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 68 Glu Gly Tyr Gly Asn Asp Ala Phe Asp Ile 1 5 10 <210> 69 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 69 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 70 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 70 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 71 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 71 Gln Gln Ser Tyr Ser Thr Pro Pro Thr 1 5 <210> 72 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 72 Ser Tyr Gly Met His 1 5 <210> 73 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 73 Ala Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 74 <211> 12 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 74 Asp Met Gly Leu Ser Trp Tyr Gly Glu Phe Asp Tyr 1 5 10 <210> 75 <211> 13 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 75 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Ser 1 5 10 <210> 76 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 76 Tyr Asp Asp Leu Leu Pro Ser 1 5 <210> 77 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 77 Ala Ala Trp Asp Asp Ser Leu Asn Trp Val 1 5 10 <210> 78 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 78 Ser Tyr Gly Met His 1 5 <210> 79 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 79 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 80 <211> 6 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 80 Asp Ile Phe Met Asp Val 1 5 <210> 81 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 81 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 82 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 82 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 83 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 83 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val Val 1 5 10 <210> 84 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 84 Asp Tyr Gly Met His 1 5 <210> 85 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 85 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 86 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 86 Ala Tyr Gly Glu Gly Gly Phe Asp Pro 1 5 <210> 87 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 87 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 88 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 88 Glu Val Ser Asn Arg Pro Ser 1 5 <210> 89 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 89 Ser Ser Tyr Thr Ser Ser Ser Thr Thr Trp Val 1 5 10 <210> 90 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 90 Ser Tyr Ala Met His 1 5 <210> 91 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 91 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Pro Val Lys 1 5 10 15 Gly <210> 92 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 92 Gly Gly Asp Gly Tyr Asn Trp Asp Ala Phe Asp Ile 1 5 10 <210> 93 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 93 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <210> 94 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 94 Ser Asn Asn Gln Arg Pro Ser 1 5 <210> 95 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 95 Ala Ala Trp Asp Asp Ser Leu Asn Ala Leu Val 1 5 10 <210> 96 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 96 Asp Tyr Ala Met His 1 5 <210> 97 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 97 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 98 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 98 Glu Gly Arg Tyr Gly Gly Phe Asp Tyr 1 5 <210> 99 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 99 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 100 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 100 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 101 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 101 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 102 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 102 Asp Tyr Ala Met His 1 5 <210> 103 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 103 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 104 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 104 Glu Gly Glu Tyr Ser Tyr Gly Gly Gly Glu Phe Asp Pro 1 5 10 <210> 105 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 105 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 106 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 106 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 107 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 107 Ser Ser Tyr Thr Ser Ser Ser Thr Trp Val 1 5 10 <210> 108 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 108 Ser Tyr Gly Met His 1 5 <210> 109 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 109 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 110 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 110 Thr Pro Gly Gly Leu Thr Pro Phe Asp Tyr 1 5 10 <210> 111 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 111 Ser Gly Ser Ser Ser Asn Ile Gly Gly Asn Thr Val Asn 1 5 10 <210> 112 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 112 Ser Asn Asn Gln Arg Pro Ser 1 5 <210> 113 <211> 13 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 113 Ala Ala Trp Asp Asp Ser Leu Asn Gly Pro Asn Val Val 1 5 10 <210> 114 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 114 Asp Tyr Ala Met His 1 5 <210> 115 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 115 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 116 <211> 12 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 116 Asp Ile Ala Gly Gly Asp Tyr Pro Val Phe Asp Tyr 1 5 10 <210> 117 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 117 Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala 1 5 10 <210> 118 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 118 Lys Ala Ser Ser Leu Glu Ser 1 5 <210> 119 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 119 Gln Gln Tyr Asn Ser Tyr Ser Pro Trp Thr 1 5 10 <210> 120 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 120 Ser Tyr Ala Met Ser 1 5 <210> 121 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 121 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 122 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 122 Glu Ser Tyr Tyr Asp Ser Ser Gly Tyr Thr Thr 1 5 10 <210> 123 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 123 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 124 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 124 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 125 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 125 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val 1 5 10 <210> 126 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 126 Asp Tyr Ala Met His 1 5 <210> 127 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 127 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 128 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 128 Ala Gln Tyr Tyr Tyr Asp Ser Ser Gly Ser Tyr Val Gly Glu Ser Phe 1 5 10 15 Asp Tyr <210> 129 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 129 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 130 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 130 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 131 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 131 Gln Gln Ser Tyr Ser Thr Pro Thr 1 5 <210> 132 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 132 Ser Tyr Ala Met His 1 5 <210> 133 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 133 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 134 <211> 11 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 134 Glu Leu Tyr Tyr Gly Pro Gly Gly Met Asp Val 1 5 10 <210> 135 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 135 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 136 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 136 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 137 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 137 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Val 1 5 10 <210> 138 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 138 Asn Tyr Ala Met Ser 1 5 <210> 139 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 139 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 140 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 140 Val Glu Val Ser Ser Trp Tyr Glu Asn Trp Phe Asp Pro 1 5 10 <210> 141 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 141 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 142 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 142 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 143 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 143 Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <210> 144 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 144 Ser Tyr Ala Met His 1 5 <210> 145 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 145 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 146 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 146 Asp Ser Gly Val Val Met Asp Tyr 1 5 <210> 147 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 147 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 148 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 148 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 149 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 149 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <210> 150 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 150 Ser Tyr Ala Met Ser 1 5 <210> 151 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 151 Ala Ile Ser Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 152 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 152 Val Gly Met Val Gln Gly Ala Arg Asn Trp Phe Asp Pro 1 5 10 <210> 153 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 153 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 154 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 154 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 155 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 155 Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <210> 156 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 156 Ser Tyr Ala Met Ser 1 5 <210> 157 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 157 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 158 <211> 10 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 158 Val Arg Val Ser Asp Gly Arg Phe Asp Tyr 1 5 10 <210> 159 <211> 17 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 159 Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu 1 5 10 15 Ala <210> 160 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 160 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 161 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 161 Gln Gln Tyr Tyr Ser Thr Pro Thr 1 5 <210> 162 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 162 Ser Tyr Ala Met His 1 5 <210> 163 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 163 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 164 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 164 Asp Thr Ile Leu Ile Asp 1 5 <210> 165 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 165 Arg Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 166 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 166 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 167 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 167 Met Gln Ala Leu Gln Thr Pro Ile Thr 1 5 <210> 168 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 168 Ser Tyr Ala Met His 1 5 <210> 169 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 169 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 170 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 170 Asp Val His His Pro Asp Tyr Gly Gly Asn Ser Ala Phe Asp Tyr 1 5 10 15 <210> 171 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 171 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 172 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 172 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 173 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 173 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 174 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 174 Ser Tyr Ala Met His 1 5 <210> 175 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 175 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 176 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 176 Asp Arg Tyr Gly Asp Tyr Asp Gly Ser Ala Phe Asp Ile 1 5 10 <210> 177 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 177 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 178 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 178 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 179 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 179 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 180 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 180 Asp Tyr Ala Met His 1 5 <210> 181 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 181 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 182 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 182 Glu Gly Gly Asp Ser Asp Phe Asp Tyr 1 5 <210> 183 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 183 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 184 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 184 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 185 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 185 Gln Gln Ser Tyr Ser Thr Pro Val Thr 1 5 <210> 186 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 186 Asp Tyr Tyr Met His 1 5 <210> 187 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 187 Leu Val Asp Pro Glu Asp Gly Glu Thr Leu Tyr Ala Glu Lys Phe Gln 1 5 10 15 Gly <210> 188 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 188 Glu Pro Gln Met Val Gln Gly Pro Ser Pro Pro Asp Tyr 1 5 10 <210> 189 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 189 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Ser Tyr Val Ser 1 5 10 <210> 190 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 190 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 191 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 191 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Leu 1 5 10 <210> 192 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 192 Ser Tyr Ala Met His 1 5 <210> 193 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 193 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 194 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 194 Asp Pro Leu Tyr Gly Met Asp Val 1 5 <210> 195 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 195 Thr Gly Thr Ser Ser Asp Val Gly Asn Tyr Asn Tyr Val Ser 1 5 10 <210> 196 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 196 Glu Val Ser Lys Arg Pro Ser 1 5 <210> 197 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 197 Ala Ser Tyr Ala Asp Ser Asn Asn Leu Tyr Val 1 5 10 <210> 198 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 198 Ser Tyr Tyr Met His 1 5 <210> 199 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 199 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 200 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 200 Asp Ser Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Ala Asp Ala Phe Asp 1 5 10 15 Ile <210> 201 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 201 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 202 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 202 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 203 <211> 12 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 203 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Asp Val Val 1 5 10 <210> 204 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 204 Ser Tyr Tyr Met His 1 5 <210> 205 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 205 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 206 <211> 12 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 206 Asn Val Pro Gly Asp Tyr Glu Val Gly Phe Asp Tyr 1 5 10 <210> 207 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 207 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 208 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 208 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 209 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 209 Gln Ser Tyr Asp Ser Ser Leu Ser Ala Val Val 1 5 10 <210> 210 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 210 Asp Tyr Ala Met His 1 5 <210> 211 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 211 Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 212 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 212 Asp Thr Thr Trp Gly Gly Ser Tyr Pro Tyr Phe Asp Tyr 1 5 10 <210> 213 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 213 Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala 1 5 10 <210> 214 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 214 Lys Ala Ser Ser Leu Glu Ser 1 5 <210> 215 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 215 Gln Gln Tyr Asn Ser Tyr Ser Pro Leu Ala 1 5 10 <210> 216 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 216 Asp Tyr Tyr Met Ser 1 5 <210> 217 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 217 Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 218 <211> 10 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 218 Leu Ser Thr Val Thr Arg Ala Phe Asp Ile 1 5 10 <210> 219 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 219 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 1 5 10 <210> 220 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 220 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 221 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 221 Gln Gln Ala Asn Ser Phe Pro Pro Thr 1 5 <210> 222 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 222 Asn Ala Trp Met Ser 1 5 <210> 223 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 223 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 224 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 224 Asn Glu Gly Gly Asp Ala Phe Asp Ile 1 5 <210> 225 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 225 Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn 1 5 10 15 <210> 226 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 226 Lys Val Ser Asn Arg Asp Ser 1 5 <210> 227 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 227 Met Gln Gly Thr His Trp Pro Leu Thr 1 5 <210> 228 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 228 Asn Tyr Ala Met His 1 5 <210> 229 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 229 Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 230 <211> 10 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 230 Glu Asp Pro Arg Arg Gly Gly Ile Asp Tyr 1 5 10 <210> 231 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 231 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 232 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 232 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 233 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 233 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val 1 5 10 <210> 234 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 234 Ser Tyr Ala Ile Ser 1 5 <210> 235 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 235 Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Ser Gln 1 5 10 15 Gly <210> 236 <211> 14 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 236 Glu Ser Gly Ser Gly Asn Arg Ile Pro Tyr Gly Met Asp Val 1 5 10 <210> 237 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 237 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 238 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 238 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 239 <211> 12 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 239 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Pro Val Val 1 5 10 <210> 240 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 240 Ser Tyr Ala Met His 1 5 <210> 241 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 241 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 242 <211> 15 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 242 Asp Ala Leu Tyr Asn Tyr Tyr Gly Ser Gly Ser His Phe Asp Tyr 1 5 10 15 <210> 243 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 243 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 244 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 244 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 245 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 245 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 246 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 246 Ser Tyr Ala Met His 1 5 <210> 247 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 247 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 248 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 248 Asp Lys Gly Asp Ser Ser Phe Asp Tyr 1 5 <210> 249 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 249 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 250 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 250 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 251 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 251 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Val Val 1 5 10 <210> 252 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 252 Ser Tyr Ala Met His 1 5 <210> 253 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 253 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 254 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 254 Asp Gln Tyr Asp Ile Leu Thr Gly Tyr Gly Gly Thr Ala Leu Asp Tyr 1 5 10 15 <210> 255 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 255 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 256 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 256 Glu Val Ser Lys Arg Pro Ser 1 5 <210> 257 <211> 10 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 257 Ser Ser Tyr Ala Gly Ser Asn Asn Leu Val 1 5 10 <210> 258 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 258 Ser Tyr Ala Met His 1 5 <210> 259 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 259 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 260 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 260 Glu Ala Gly Glu Gly Val Asp Tyr 1 5 <210> 261 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 261 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 262 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 262 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 263 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 263 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val 1 5 10 <210> 264 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 264 Ser Tyr Ala Met His 1 5 <210> 265 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 265 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 266 <211> 15 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 266 Glu Ser Ala Tyr Ser Ser Ser Trp Ser Gly Leu Arg Phe Asp Pro 1 5 10 15 <210> 267 <211> 14 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 267 Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <210> 268 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 268 Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 269 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 269 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Tyr Val 1 5 10 <210> 270 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 270 Ser Tyr Ala Met His 1 5 <210> 271 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 271 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 272 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 272 Gly Gly Ala Val Ala Gly Gly Trp Tyr Phe Asp Tyr 1 5 10 <210> 273 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 273 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 1 5 10 <210> 274 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 274 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 275 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 275 Gln Gln Ala Asn Ser Phe Pro Pro Thr 1 5 <210> 276 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 276 Ser Tyr Ala Met His 1 5 <210> 277 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 277 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 278 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 278 Ser Gly Ser Tyr Phe Gly Phe Asp Tyr 1 5 <210> 279 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 279 Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 280 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 280 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 281 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 281 Met Gln Ala Leu Gln Thr Pro Leu Thr 1 5 <210> 282 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 282 Ser Tyr Ala Met His 1 5 <210> 283 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 283 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Gly Ser Val Lys 1 5 10 15 Gly <210> 284 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 284 Asp Trp Arg Gly Val Tyr Phe Asp Tyr 1 5 <210> 285 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 285 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 286 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 286 Glu Val Ser Asn Arg Pro Ser 1 5 <210> 287 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 287 Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <210> 288 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 288 Ser Tyr Gly Ile Ser 1 5 <210> 289 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 289 Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <210> 290 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 290 Trp Gly Val Val Gly Gly Met Asp Val 1 5 <210> 291 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 291 Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 1 5 10 <210> 292 <211> 7 <212> PRT <213> Synthetic Sequence <220> <223> LCDR 2 <400> 292 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 293 <211> 9 <212> PRT <213> Synthetic Sequence <220> <223> LCDR 3 <400> 293 Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <210> 294 <211> 5 <212> PRT <213> Synthetic Sequence <220> <223> HCDR 1 <400> 294 Ser Tyr Gly Met His 1 5 <210> 295 <211> 17 <212> PRT <213> Synthetic Sequence <220> <223> HCDR 2 <400> 295 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 296 <211> 8 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 296 Asp Phe Ser Asp Ala Phe Asp Ile 1 5 <210> 297 <211> 13 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 297 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Ser 1 5 10 <210> 298 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 298 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 299 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 299 Gly Thr Trp Asp Ser Ser Leu Ser Ala Val Val 1 5 10 <210> 300 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 300 Ser Tyr Gly Met His 1 5 <210> 301 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 301 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 302 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 302 Gly Ser Gly Trp Tyr Phe Asp Tyr 1 5 <210> 303 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 303 Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala 1 5 10 <210> 304 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR 2 <400> 304 Lys Ala Ser Ser Leu Glu Ser 1 5 <210> 305 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR 3 <400> 305 Gln Gln Tyr Asn Ser Tyr Ser Trp Thr 1 5 <210> 306 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR 1 <400> 306 Ser Tyr Tyr Met His 1 5 <210> 307 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR 2 <400> 307 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 308 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> HCDR 3 <400> 308 Asp Asp Tyr Gly Asp Tyr 1 5 <210> 309 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR 1 <400> 309 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 310 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 310 Glu Val Ser Asn Arg Pro Ser 1 5 <210> 311 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 311 Ser Ser Tyr Thr Ser Ser Ser Phe Ser 1 5 <210> 312 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 312 Ser Tyr Tyr Met His 1 5 <210> 313 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 313 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 314 <211> 12 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 314 Asp Ser Ser Ser Gly Trp Ser Ser Tyr Phe Asp Tyr 1 5 10 <210> 315 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 315 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 316 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 316 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> 317 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 317 Gln Gln Tyr Asp Asn Leu Pro Leu Thr 1 5 <210> 318 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 318 Ser Tyr Tyr Met His 1 5 <210> 319 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 319 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 320 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 320 Met Thr Thr Ser Leu Gly Phe Asp Tyr 1 5 <210> 321 <211> 11 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 321 Arg Ala Ser Gln Gly Ile Ser Asn Trp Leu Ala 1 5 10 <210> 322 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 322 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 323 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 323 Gln Gln Ala Asn Ser Leu Pro Leu Thr 1 5 <210> 324 <211> 5 <212> PRT <213> Artificial sequence <220> <223> HCDR 1 <400> 324 Ser Tyr Tyr Met His 1 5 <210> 325 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR 2 <400> 325 Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 326 <211> 9 <212> PRT <213> Artificial sequence <220> <223> HCDR 3 <400> 326 Ser Arg Gly Gly Ser Ala Phe Asp Ile 1 5 <210> 327 <211> 16 <212> PRT <213> Artificial sequence <220> <223> LCDR 1 <400> 327 Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 328 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR 2 <400> 328 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 329 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR 3 <400> 329 Met Gln Ala Leu Gln Thr Pro Leu Thr 1 5 <210> 330 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Epitope 1 <400> 330 Asn Lys Gly Leu Thr Leu Leu Asp Gly Asp Leu Pro Glu Gln Glu 1 5 10 15 <210> 331 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Epitope 2 <400> 331 Gln Tyr Pro Pro Glu Lys Ile Ala Ser Glu Leu Lys Asp Thr Ile 1 5 10 15 <210> 332 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Epitope 5 <400> 332 Ala Lys Pro Ser Leu Leu Ser Arg Val Gly Ala Leu Thr Asn Thr 1 5 10 15 <210> 333 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Epitope 6 <400> 333 Glu Val Arg Val Pro Trp Leu His Ser Leu Ala Ala Ala Gln Glu 1 5 10 15 <210> 334 <211> 118 <212> PRT <213> Artificial sequence <220> <223> VH <400> 334 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Ala Ala Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 335 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 335 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 336 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 336 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Gly Phe Arg Arg Leu Phe Asp Pro Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 337 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 337 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 338 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 338 Gln Val Gln Leu Val Gln Ser Gly Gly Ser Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Phe Ala Ser Ile Ala Ala Arg Pro Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 339 <211> 111 <212> PRT <213> Artificial sequence <220> <223> VL <400> 339 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Arg Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 340 <211> 116 <212> PRT <213> Artificial sequence <220> <223> VH <400> 340 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ser Ser Asn Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 341 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 341 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 342 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 342 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Asn Pro Ser Ser Gly Ala Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 343 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 343 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 344 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 344 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser His Ser Ser Gly Trp Glu Trp Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 345 <211> 110 <212> PRT <213> Artificial sequence <220> <223> VL <400> 345 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 346 <211> 123 <212> PRT <213> Artificial sequence <220> <223> VH <400> 346 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Leu Tyr Cys Ser Gly Gly Ser Cys Tyr Ser Ala Leu Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 347 <211> 111 <212> PRT <213> Artificial sequence <220> <223> VL <400> 347 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Arg Tyr Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 348 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 348 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Asp Gly Ser Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 349 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL <400> 349 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 350 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 350 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Tyr Gly Asn Asp Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 351 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 351 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 352 <211> 121 <212> PRT <213> Artificial sequence <220> <223> VH <400> 352 Gln Val Gln Leu Val Glu Phe Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Gly Leu Ser Trp Tyr Gly Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 353 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 353 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Ser Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 354 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 354 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Phe Met Asp Val Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> 355 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 355 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 356 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 356 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ala Cys Val Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Tyr Gly Glu Gly Gly Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 357 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 357 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 358 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 358 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Arg Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Pro Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Gly Tyr Asn Trp Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 359 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 359 Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Ala Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 360 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 360 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Arg Tyr Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 361 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL <400> 361 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 362 <211> 122 <212> PRT <213> Artificial sequence <220> <223> VH <400> 362 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Glu Tyr Ser Tyr Gly Gly Gly Glu Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 363 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 363 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 364 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 364 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asn Thr Pro Gly Gly Leu Thr Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 365 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 365 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Gly Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Pro Asn Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 366 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 366 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Ala Gly Gly Asp Tyr Pro Val Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 367 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 367 Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 368 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 368 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu Ser Tyr Tyr Asp Ser Ser Gly Tyr Thr Thr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 369 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 369 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 370 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 370 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Gln Tyr Tyr Tyr Asp Ser Ser Gly Ser Tyr Val Gly Glu 100 105 110 Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 371 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 371 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 372 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 372 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Tyr Tyr Gly Pro Gly Gly Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 373 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 373 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 374 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 374 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Glu Val Ser Ser Trp Tyr Glu Asn Trp Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 375 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 375 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 376 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 376 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Val Val Met Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 377 <211> 110 <212> PRT <213> Artificial sequence <220> <223> VL <400> 377 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 378 <211> 122 <212> PRT <213> Artificial sequence <220> <223> VH <400> 378 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Ala Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Gly Met Val Gln Gly Ala Arg Asn Trp Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 379 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 379 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 380 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 380 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Arg Val Ser Asp Gly Arg Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 381 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 381 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 Tyr Ser 20 25 30 Ser Asn Asn 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 Tyr Tyr Ser Thr Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 382 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 382 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Ser 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Asp Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Val Lys Asp Thr Ile Leu Ile Asp Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 383 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 383 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110 <210> 384 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 384 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Val His His Pro Asp Tyr Gly Gly Asn Ser Ala Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 385 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL <400> 385 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 386 <211> 122 <212> PRT <213> Artificial sequence <220> <223> VH <400> 386 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Tyr Gly Asp Tyr Asp Gly Ser Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 387 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 387 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 388 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 388 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Gly Asp Ser Asp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 389 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 389 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Val 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105 <210> 390 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 390 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Thr 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Ser Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Leu Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Val Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Glu Pro Gln Met Val Gln Gly Pro Ser Pro Pro Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 391 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 391 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Ser Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 392 <211> 117 <212> PRT <213> Artificial sequence <220> <223> VH <400> 392 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Pro Leu Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 393 <211> 111 <212> PRT <213> Artificial sequence <220> <223> VL <400> 393 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asn Tyr 20 25 30 Asn Tyr Val Ser Trp Phe Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Tyr Ala Asp Ser 85 90 95 Asn Asn Leu Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 394 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 394 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Ala Asp Ala 100 105 110 Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125 <210> 395 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL <400> 395 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Asp Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 396 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 396 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Pro Gly Asp Tyr Glu Val Gly Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 397 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 397 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 398 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 398 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Thr Thr Trp Gly Gly Ser Tyr Pro Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 399 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 399 Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Pro 85 90 95 Leu Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 400 <211> 119 <212> PRT <213> Artificial sequence <220> <223> VH <400> 400 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ser Thr Val Thr Arg Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 401 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL <400> 401 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 402 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 402 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Gln Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Asn Glu Gly Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110 Met Val Thr Val Ser Ser 115 <210> 403 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 403 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30 Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 404 <211> 119 <212> PRT <213> Artificial sequence <220> <223> VH <400> 404 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asp Pro Arg Arg Gly Gly Ile Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 405 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 405 Gln Ser Val Leu Thr Gln Pro Pro Pro Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 406 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 406 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Ser 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Ser Gly Ser Gly Asn Arg Ile Pro Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 407 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 407 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Pro Val Val Phe Gly Gly Gly Thr Gln Val Thr Val Leu 100 105 110 <210> 408 <211> 124 <212> PRT <213> Artificial sequence <220> <223> VH <400> 408 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Leu Tyr Asn Tyr Tyr Gly Ser Gly Ser His Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 409 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 409 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 410 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 410 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Lys Gly Asp Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 411 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 411 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 412 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 412 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gln Tyr Asp Ile Leu Thr Gly Tyr Gly Gly Thr Ala Leu 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 413 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 413 Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Glu Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Asn Asn Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 414 <211> 117 <212> PRT <213> Artificial sequence <220> <223> VH <400> 414 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Ala Gly Glu Gly Val Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 415 <211> 111 <212> PRT <213> Artificial sequence <220> <223> VL <400> 415 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 416 <211> 124 <212> PRT <213> Artificial sequence <220> <223> VH <400> 416 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Glu Ser Ala Tyr Ser Ser Ser Trp Ser Gly Leu Arg Phe Asp 100 105 110 Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 417 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 417 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 418 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 418 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ala Val Ala Gly Gly Trp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 419 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 419 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 420 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 420 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Ser Tyr Phe Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 421 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 421 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 422 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 422 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Trp Arg Gly Val Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 423 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 423 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 424 <211> 118 <212> PRT <213> Artificial sequence <220> <223> VH <400> 424 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Trp Gly Val Val Gly Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 425 <211> 107 <212> PRT <213> Artificial sequence <220> <223> VL <400> 425 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105 <210> 426 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 426 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Phe Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met 100 105 110 Val Thr Val Ser Ser 115 <210> 427 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 427 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 428 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 428 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Gly Trp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 429 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 429 Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 430 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 430 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 431 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 431 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Pro Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Phe Ser Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 <210> 432 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 432 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Ser Ser Gly Trp Ser Ser Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 433 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 433 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 434 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 434 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Thr Thr Ser Leu Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 435 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 435 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Leu Lys Pro Gly Lys Ala Pro Lys Leu Leu Val 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 436 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 436 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Arg Gly Gly Ser Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 437 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 437 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105 110 <210> 438 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Linker <400> 438 Gly Gly Ser Gly Gly Ser 1 5 <210> 439 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Linker <400> 439 Ala Ala Ala Ala Ala 1 5 Brief Description of the Drawings

[0236] The present invention will now be further described by reference to the following drawings.

[0237] Figure 1 : Label the membranes of lipid droplets with IgG autoantibodies from patients with Lawrence syndrome / AGL.

[0238] In addition to fluorescence labeling, 10 nm gold particles are used in an electron microscope (EM) and 1 nm gold is used in an optical microscope (LM) to achieve visualization.

[0239] A) Optical microscopy of single-vacuole adipocytes in human white adipose tissue. Silver-enhanced gold particles are only present on the membrane of the lipid vacuole, which cannot be distinguished from the plasma membrane at this magnification. The loose connective tissue between adipocytes is not stained. Scale bar 25 μm.

[0240] B) Fluorescence microscopy of multi-vacuole 3T3-L1 cells. Labeling is visualized by the cyanine dye Cy3. Scale bar 50 μm.

[0241] C, D) Transmission electron microscopy (TEM) of 3T3-L1 cells. The surface of the lipid storage droplets is densely labeled with gold particles. Only sporadic gold particles (white arrows) are present on the plasma membrane, and no gold particles are present on the nuclear envelope. Scale bar 1 μm.

[0242] E) No labeling is observed in 3T3-L1 cells at the preadipocyte stage. Scale bar 1 μm.

[0243] F) Freeze-fracture replica of 3T3-L1 cells. Gold labeling appears in the phospholipid layer (P-face, white arrow). There is no labeling on the surface of the internal droplets in the protrusions (equivalent to the E-face, black arrow) and in the nucleus of LSD. Scale bar 0.3 μm.

[0244] G) Freeze-fracture replica of the exoplasmic fracture face of the plasma membrane of 3T3-L1 cells, characterized by elevated microvesicles. Gold particles are not visible. Scale bar 0.2 μm.

[0245] H) TEM examination of mouse adipose tissue. Gold particles are deposited on the surface of LSD (white arrow). The dashed line indicates the plasma membrane of adipocytes. Tissue eosinophils are present nearby.

[0246] C, caveolae; core, lipid core of LSD; EF (exoplasmic fracture face), exoplasmic fracture face; EOSG (eosinophil granule), eosinophil granule; LSD (lipid storage droplet), lipid storage droplet; N (nucleus), cell nucleus; PM (plasma membrane), plasma membrane. Scale bar 0.5 μm. The images shown represent at least 3 independent experiments.

[0247] Figure 2 : Human anti-fat autoantibodies react with multiple perilipin-1 variants.

[0248] A) Two-dimensional separation of proteins from rat adipose cell membranes. Proteins are separated in the first dimension in a linear pH gradient IPG strip (pH 4 - 7). In the second dimension, a 10% (w / v) homogeneous SDS PAGE gel is used to separate proteins. Spots detected by Coomassie staining are shown in green. Spots detected by anti-fat autoantibodies on a parallel blot are color-coded in red. Immunoreactive spots are identified in yellow (marked with arrows). Spot numbers refer to the identification numbers listed in Table B.

[0249] B) Summary of peptide mass fingerprint (PMF) analysis of protein spots. Three of the five analyzed spots were unambiguously identified as perilipin A (spots 1, 2, and 4), and two spots were identified as perilipin B (spots 4 and 5), respectively, which are produced by alternative splicing of the perilipin-1 transcript. Acc.-Nr. is the sequence identification number in GenBank. The theoretical molecular weights indicated in the fourth column were calculated from the amino acid sequences. PMF spectra were submitted for identification using the Mascot interface (Mascot 2.1.03), and Mascot scores (P = 0.05) are depicted.

[0250] C) Comparison of human anti-fat IgG with a commercial anti-perilipin-1 antibody (Affinity BioReagents, Golden, Colorado, USA). 10 μg of membrane protein was subjected to SDS-PAGE and immunoblotting (↓) after cutting the PVDF membrane between two lanes of membrane proteins. Incubation with the patient's autoantibody and the anti-perilipin-1 antibody showed positive bands of the same pattern.

[0251] Figure 3 : Autoantibodies do not interfere with the homeostasis of lipid storage in differentiated human preadipocytes.

[0252] Human preadipocytes were induced to undergo adipogenic conversion and allowed to accumulate triacylglycerol over 14 days. In the presence of 10 nM insulin, these cells were loaded with a fluorescently labeled fatty acid (NBD-FA) for 3 hours. After washing to remove excess NBD-FA, the cells were incubated for 3 hours (A, C, E) or 15 hours (B, D, F) in the presence of 10 nM insulin in the absence of antibody (white bars), in the presence of anti-fat IgG (black bars), or in the presence of control IgG (gray bars). Cells were harvested, total lipids were extracted, and aliquots were analyzed by thin-layer chromatography, followed by fluorescence scanning to quantify the labeled intracellular lipids. The results shown are the mean ± SEM of 4 experiments.

[0253] A, B) Anti-fat IgG does not interfere with the accumulation of NBD-FA in the total cellular lipid pool, expressed as relative fluorescence units (RFU).

[0254] C, D) Autoantibodies have no effect on the distribution of incorporated NBD-FA between the stored triacylglycerol pools

[0255] E, F) Autoantibodies have no effect on the distribution of incorporated NBD-FA between the pools of diacylglycerols (DAGs) and monoacylglycerols (MAGs), the intermediates of lipid synthesis and degradation.

[0256] Figure 4 . In the presence of serum, anti-fat autoantibodies accumulate in cells with an atypical morphology (dead cells).

[0257] When cells were washed thoroughly before fixation and immunofluorescence detection, exposure of 3T3-L1 adipocytes to control IgG and anti-fat IgG in serum-free medium resulted in barely detectable cell labeling (A, F). However, anti-fat IgG (G-J), but not control IgG (B-E), resulted in immunoreactivity in a significant proportion of cells in the presence of goat serum (not heat-inactivated). This effect was strongly dose-dependent. Closer examination revealed that under these conditions, anti-fat IgG did not visibly accumulate on the surface of lipid droplets (N), but in cells with atypical morphology (arrows, staining unrelated to lipid droplets, condensed chromatin), which are rarely found in normal cultures of 3T3-L1 adipocytes. It should be noted that the typical staining pattern of lipid droplets around the nuclei of cells fixed and stained according to the normal protocol (L, M). (K) No immunoreactivity in fixed cells with control IgG. (A-J, N) Live cells incubated with the first antibody, (K-M) fixed cells incubated with the first antibody. (M, N) Overlay of the indicated regions of the fluorescence images (J and L, respectively) and the corresponding phase-contrast images; the red channel was set to twice the intensity for better visibility in the overlay image. Scale bars: 250 μm (A-L) or 100 μm (M-N).

[0258] Figure 5 . Anti-fat autoantibodies trigger complement-dependent cell death in 3T3-L1 cells.

[0259] 3T3-L1 adipocytes were generated in a serum-free differentiation system and allowed to accumulate lipids until day 8 after induction of differentiation. As shown, cells were pre-incubated with anti-fat IgG or control IgG for 40 min. Then, as shown, medium without (control) or containing rabbit complement (final dilutions of 1:64 or 1:32) was added. In the presence of complement, 1:32 anti-fat IgG was additionally tested at twice the concentration normally used (anti-fat IgG 2x).

[0260] A) Cells were fixed and stained with Fluoro Quench AO / EB reagent, which resulted in green staining of live cells and orange staining of dying and dead cells (in flattened adipocytes, lipid droplets appeared unstained, while in round adipocytes, they were only visible). Scale bars for all images were 100 μm.

[0261] B) Quantification of 3 independent experiments showed a significant number of dead cells in the presence of anti-fat IgG plus complement, but not under control conditions. Significant differences from all corresponding controls were identified by ANOVA (P < 0.005) with Student-Newman-Keuls all-pairwise multiple comparisons, **, P < 0.01; ***, P < 0.001.

[0262] C) Percentage of viable cells relative to the corresponding untreated control after 1 hour (Student’s t-test; #, P < 0.05).

[0263] Figure 6 . Protocol for perilipin-1-dependent antibody-induced complement activation.

[0264] Mechanism of action of the induced complement response against adipocytes mediated by anti-perilipin-1 antibodies. The perilipin-1 peptide is degraded by the proteasome, and the resulting perilipin-1 fragments are presented by MHC on the cell surface of adipocytes. Antibodies targeting the peptide sequence, i.e., having an epitope of any one of SEQ ID NO: 1-6, 330-333. As disclosed herein, specifically target adipocytes and allow for the specific elimination of adipocytes by complement activation (indirect elimination mechanism). Alternatively, cytotoxic T cells specific for at least one perilipin-1 epitope can eliminate adipocytes presenting said perilipin-1 by an indirect elimination mechanism.

[0265] In addition, other effector systems that can be activated by antibodies that bind to MHC of perilipin-1 fragments can employ a direct elimination mechanism. These effector systems activated by binding of the adipocyte-binding antibody mediated by the Fc receptor can be macrophages or neutrophils (neutrophilic polymorphonuclear cells).

[0266] Figure 7 . Anti-fat autoantibodies bind lipid-associated proteins.

[0267] Lipid-associated proteins (1) and cytosolic proteins (2) of isolated adipocytes from rat fat pads were separated by SDS-PAGE and stained with Coomassie blue (A) or transferred to a PVDF membrane (B). Anti-fat IgG reacted with two major bands and several minor bands of the preparation containing lipid-associated proteins. (C) The control membrane was cut along the molecular weight standard lane (↓) and incubated with control serum, then with protein A / G-AP (control IgG), or with protein A / G-AP alone (protein A / GAP), indicating that the recognition of the bands in (B) is specific for anti-fat antibodies. S, molecular weight standard. Data represent 5 experiments with rat fat pads, and similar results were obtained with in vitro differentiated human adipocytes and mouse 3T3-L1 cells.

[0268] Figure 8 . Only a fraction of cells are sensitive to autoantibody-triggered cell death.

[0269] With Figure 5The experiments summarized herein were conducted in parallel with cells, but the incubation was continued for 24 hours. Additionally, (A) shows the data obtained with a higher complement concentration (final dilution 1:16). Quantification of 3 independent experiments demonstrated significant cell loss in the presence of anti-adiponectin IgG plus complement, but not under control conditions. When comparing the number of dead cells (B) and live cells (C), there was a significant difference due to the separation of dead cells. (B) Significant differences from all corresponding controls were identified by ANOVA (p = 0.016) with Student-Newman-Keuls all pairwise multiple comparisons; *, P < 0.05. (C) Percentage of live cells relative to the corresponding untreated control after 24 hours (Student’s t test; #, P < 0.05, ##, P < 0.005).

[0270] Figure 9 . Peptide arrays of adiponectin-1 epitopes.

[0271] Peptide arrays (PEPperPRINT, PEPperMAP) with adiponectin-1 autoantibodies were used to identify adiponectin-1 epitopes having any one of SEQ ID NO: 1-6, 330-333. The sequences of human adiponectin 1-5 were extended at the N-terminus and C-terminus with neutral linker sequences to prevent peptide shortening. The extended antigen sequences were translated into peptide sequences each having 15 amino acids, wherein the peptide sequences each had an overlap of 14 amino acids. The peptide arrays were generated by screening with the adiponectin-1 autoantibodies described in the foregoing embodiments. Antibody specificity was verified by screening all possible 15-mer peptide sequences of adiponectin-1 related proteins adiponectin-2, adiponectin-3, adiponectin-4, and adiponectin-5, which are involved in lipid storage and / or different functions in other cells. Thus, cross-reactivity with other members of the adiponectin family was excluded.

[0272] A) Peptide arrays were analyzed with human anti-adiponectin-1 autoantibodies to identify adiponectin-1 epitopes. Only adiponectin-1 peptides bound specifically and with high affinity.

[0273] B) Quantification of antibody binding. Six peptides bound with high affinity. Binding of the peptides depicted on the right (PEKEPPKP from adiponectin-3 and PILVERPEP from adiponectin-5) was negligible.

[0274] Multiple identified peptides (epitopes) were highly conserved in the mouse and human sequences.

[0275] Figure 10 . Representative flow cytometry fluorescence histograms (dark gray curves) of anti-adiponectin antibodies bound to primary adipocytes.

[0276] Antibodies 17 - 20 (A), 21, 22, 24, and 25 (B) were analyzed. The control represents cells treated with isotype control and secondary antibody (light gray curve). As a control, a commercial antibody against perilipin - 1 from Abcam (ab192716) was used (C). The overlapping histograms observed with the commercial antibody (C) indicate that the commercial anti - perilipin - 1 antibody does not bind specifically to adipocytes. In contrast, the antibodies of the present invention show binding to adipocytes (right - shifted histograms) compared to the isotype controls (A, B).

[0277] Figure 11 . Representative flow cytometry fluorescence histograms (dark gray curve) of anti - perilipin antibodies binding to primary adipocytes.

[0278] Antibodies 26 - 32 of the present invention were analyzed. The control represents cells treated with isotype control and secondary antibody (light gray curve). The antibodies of the present invention bind effectively to adipocytes compared to the isotype control.

[0279] Figure 12 . Complement - mediated cell death mediated by anti - perilipin antibodies.

[0280] Complement - mediated cell death of 3T3 - L1 cells differentiated into adipocytes after addition of the commercial antibody against perilipin - 1 from Abcam (ab192716) compared to the control (A) and after addition of a single anti - perilipin antibody (B). The live / dead cell ratio was calculated by dividing the fluorescence intensity of a fluorescent dye that stains only live cells by the fluorescence intensity of the dye that stains dead cells. The detected signals were compared to the signals of the isotype control. The signals obtained for the isotype control are represented by the dashed line. The commercially available antibody tested (PLN1 - Ab Abcam) did not show a significant difference from the signals of the isotype control and did not show significant (no significant difference: ns) complement - mediated cell death (A). In contrast, the antibodies of the present invention showed a significant difference in complement - mediated cell death (*: p < 0.05; **: p < 0.01)( Figure 12 (B). Figure 12 (B) also shows again the signals of the isotype control obtained in this experiment, as represented by the dashed line. The antibodies shown, their target epitopes, and their respective SEQ ID NO:s are listed in Table 5.

[0281] Figure 13 . Complement - mediated cell death mediated by anti - perilipin antibodies.

[0282] Fluorescence microscopy images of complement-mediated cell death of 3T3-L1 cells differentiated into adipocytes after addition of anti-perilipin antibodies such as antibody No. 20 and antibody No. 25 (B), compared with the negative control (without addition of antibody) and the isotype control antibody (A). In the presence of the anti-perilipin antibodies of the present invention, particularly antibody No. 20 or antibody No. 25, the intensity of live cell staining decreased and the number of dead cells increased. Therefore, the antibodies of the present invention show effective complement-mediated cell death.

[0283] Figure 14 . Complement-mediated cell death compared with commercial antibodies.

[0284] The mean (plus SEM) of the difference in the number of dead cells measured with and without complement is shown; the numbers at the top of the error bars represent the P values of a two-sided Student's t-test; all tested commercial antibodies showed non-significant results except for aF-Ab (aF-antibody, a polyclonal antibody from a patient). The tested commercial anti-perilipin antibodies were PA1-1052 (ThermoFisher), AF6615 (R&D Systems), CST antibody #3470 (D418), and PA5-18693 (ThermoFisher). Therefore, the commercially available antibodies do not show mediation of complement-mediated cell death.

[0285] Figure 15 . The patient-derived anti-fat antibody (aF-AB) and antibody #5 bind to the surface of adipocytes, while the commercial antibody PA1-1052 does not bind.

[0286] (A) The overall view of the total cells on the left is differently contrasted with the representation of the lipid vacuoles on the right, showing adipocytes being considered. (B) 50 μm 2 10-fold magnification of the counted sections. Left: Microvilli, right: Immunogold particles (white dots) bound by AB. (A + B) Cells incubated with aF-AB. At least 7 - 8 different cells were included for counting. (C) Quantitative evaluation. ANOVA (P = 0.00002) with multiple comparisons (Holm-Sidak, P values in the figure). An increased binding of gold particles was observed for the patient-derived anti-fat antibody (aF-AB) and the antibodies of the present invention such as antibody No. 5 compared with the control. In contrast, no significant increase in the binding of gold particles was observed for the commercially available antibody PA1-1052 compared with the control. Therefore, the antibodies of the present invention show better binding effectiveness to adipocytes than the commercially available anti-perilipin antibodies.

[0287] Figure 16 . Exemplary antigen-binding peptides of the present invention, particularly antibodies and the corresponding CDR sequences.

[0288] Describes the CDR amino acid sequences of antibodies numbered 5 - 11, 13 - 14, 16 - 58. The CDR sequences of the heavy chain (HCDR) and the light chain (LCDR) are shown. The CDR 1, CDR 2, and CDR 3 of the heavy chain (HCDR) are depicted from left to right and are each separated by "_". The CDR 1, CDR 2, and CDR 3 of the light chain (LCDR) are depicted from left to right and are each separated by "_".

[0289] Figure 17 . Exemplary antigen - binding peptides of the present invention, particularly antibodies, and the corresponding VH and VL sequences.

[0290] Depicts the VH and VL amino acid sequences of antibodies numbered 5 - 11, 13 - 14, 16 - 58.

[0291] Examples

[0292] Example 1: Isolation of autoantibodies targeting perilipin - 1.

[0293] Written informed consent was obtained from all donors of tissue samples according to the protocol approved by the Ethics Committee of the University Hospital of Jena. The stromal - vascular fraction of cells from adipose tissue samples (termed human pre - adipocytes) was isolated and cultured to confluence in Medium 199 containing 10% (v / v) fetal bovine serum [5]. 3T3 - L1 cells were obtained from ATCC and maintained to confluence in DMEM containing 10% (v / v) fetal bovine serum. All experiments involving 3T3 - L1 - cell differentiation or stimulation were conducted in serum - free medium, which was a medium composed of DMEM and Ham's F12 medium in a 3:1 ratio (without phenol red, containing 7.5 mM HEPES, pH 7.2), supplemented with gentamicin (40 μg / ml), fetuin (300 μg / ml), transferrin (2 μg / ml), pantothenate (17 μm), biotin (1 μm), and insulin (1 μm) [6]. For adipogenic conversion of 3T3 - L1 cells, this medium was further supplemented with dexamethasone (100 nM) and 3 - isobutyl - 1 - methylxanthine (500 μm). Unless otherwise indicated, all experiments involving anti - lipid IgG and live cells (including complement activation assays) were conducted under serum - free conditions. Immunoglobulin G (IgG) from 5 ml of patient serum (anti - lipid IgG) or control serum (control IgG) was purified on thiophilic agarose (AFFI - TTM; Kem - En - Tec, Taastrup, Denmark) according to the manufacturer's instructions.

[0294] Example 2: Preparation and analysis of adipocyte lipid - associated proteins.

[0295] Male Wistar rats were used. The adipocyte suspension in PBS was shaken well with half volume of chloroform. After centrifugation (2500×g) for 5 minutes at 25 °C, lipids dissolved in chloroform were separated from the supernatant, and cytoplasmic proteins and lipid-associated proteins in the fat cake at the interface of the organic and aqueous phases were isolated. The fat cake was extracted twice with chloroform. Proteins in the supernatant were precipitated with acetone at -20 °C for 1 h, and lipid-associated proteins were suspended by vortexing in PBS. Residual chloroform in the final precipitate was evaporated under vacuum. 100 μg of lipid-associated proteins or cytoplasmic proteins from adipocytes were dissolved in 100 μl of sample buffer containing 8 M urea. 10 μl of the sample was separated on a microgel at 4 °C. The gel was fixed and stained with Coomassie blue, or proteins were transferred to a PVDF membrane (Immobilon-P, 0.45 μm, Millipore, Bedford) at 1 mA / cm2 for 2 h at 8 °C using a semi-dry blotting unit. After staining with Ponceau S for 2 min, the membrane was washed with 0.1 N NaOH, rinsed with water, blocked overnight in 0.2% I-block (TROPIX, Bedford, Massachusetts) in Tris-buffered saline-Tween 20 (TBS-T), and incubated with the first antibodies for 1 h: anti-lipid IgG and control IgG were diluted at 1:1000, and polyclonal rabbit anti-perilipin-1 was diluted at 1:1250. Protein G-alkaline phosphatase (AP) was diluted at 1:5000. Anti-rabbit IgG-AP was diluted at 1:1250. The blots were developed by the nitroblue tetrazolium method. Proteomic analysis of the fat cake proteins was performed.

[0296] Example 3: Evaluation of storage lipid metabolism.

[0297] Human preadipocytes in a confluent monolayer were induced to undergo adipogenesis for 8 days in serum-free medium containing 1 μM insulin, 1 μM cortisol, 500 μM 3-isobutyl-1-methylxanthine, and 1 μM rosiglitazone, and then triglyceride accumulation was allowed in the presence of insulin alone until day 14. Lipid pools containing fatty acids, mainly triglycerides, were labeled with the fluorescent fatty acid analogue 12-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)dodecanoic acid (NBD-FA), and analyzed by thin layer chromatography and fluorescence imaging. Briefly, labeling was carried out in serum-free medium containing 1% (w / v) fatty acid-free bovine serum albumin and 100 μM NBD-FA. After washing to remove excess NBD-FA, the cells were incubated for different times in the presence or absence of antibodies. Incubation was terminated by removing the medium and immediately extracting the lipids with 2-propanol.

[0298] Example 4: Labeling the membranes of lipid droplets with IgG autoantibodies from lipodystrophic patients.

[0299] Serum containing autoantibodies against adipose tissue from AGL patients was used to identify target autoantigens. The purified IgG fraction (anti-fat IgG) of the autoimmune serum labeled only adipose tissue, but not the other tissues tested. Labeling was restricted to adipocytes in tissue sections analyzed by immunohistochemistry ( Figure 1 A). Anti-fat IgG stained adipocytes from all other mammalian species tested, except for human unilocular adipocytes, but did not stain adipocytes from chicken and carp (data not shown). Immunofluorescent staining of in vitro differentiated 3T3-L1 mouse adipocytes containing multiple lipid storage droplets (LSDs) ( Figure 1 B) showed specific reactivity of anti-fat IgG with the surface of LSDs. This specific labeling of the LSD surface was confirmed by transmission electron microscopy on immunogold-labeled ultrathin sections of differentiated 3T3-L1 cells ( Figure 1 C). The plasma membrane of adipocytes was only occasionally labeled ( Figure 1 D), and undifferentiated cells showed no labeling at all ( Figure 1 E), indicating that the expression of the autoantigen was almost restricted to the LSDs of adipocytes. These findings were confirmed in ultrathin sections from mouse adipose tissue ( Figure 1 H).

[0300] Example 5: Anti-fat autoantibodies were found to react with lipid-associated proteins identified as multiple perilipin-1 variants.

[0301] Adipocytes from isolated rat epididymal fat pads were used to prepare defatted and cytosolic fractions of lipid-associated proteins. In Western blot experiments using anti-fat IgG, a characteristic pattern of two major and several minor bands was found almost exclusively in the fraction of lipid-associated proteins ( Figure 7 B). Since IgG from healthy controls and protein A / G-AP alone did not react with these bands ( Figure 7 C), the recognition of this band pattern was specific for anti-fat autoantibodies. Thus, fractionation of rat adipocytes confirmed the results of microscopic analysis. After it had been confirmed that anti-fat IgG specifically labeled the putative autoantigen from adipocytes, identification of the autoantigen was initiated. After separation of the lipid-associated protein fraction by two-dimensional electrophoresis, several groups of immunoreactive spots were identified by anti-fat IgG ( Figure 2 A). These spots were excised, subjected to trypsin digestion, and the peptides were subsequently analyzed by MALDI-TOF-MS. Searching the NCBI protein database using the mass spectrometry data identified all immunoreactive spots as variants of perilipin-1 ( Figure 2B). A direct comparison of anti-fat IgG and a commercial anti-perilipin-1 antibody revealed the same staining pattern in Western blot analysis, confirming that perilipin-1 is the adipocyte-specific autoantigen in AGL. Figure 2 C).

[0302] Example 6: Anti-fat autoantibodies accumulate in cells with atypical morphology in the presence of serum.

[0303] To obtain information on the mechanism by which anti-fat IgG causes adipocyte loss, it was evaluated whether anti-fat IgG interferes with stored lipid metabolism in intact cells. Thus, cells were labeled with a fluorescent fatty acid (NBD-FA), which is a substrate for both lipogenic and lipolytic enzymes. During a 3-h or 15-h incubation, neither control IgG nor anti-fat IgG altered the total amount of labeled lipid. Figure 3 A, Figure 3 B). For stored triglycerides Figure 3 C, Figure 3 D) and the lipolytic intermediates diacylglycerol and monoacylglycerol Figure 3 E, Figure 3 F), more specific examinations also revealed no effect of anti-fat IgG in in vitro differentiated human adipocytes. Thus, based on the almost exclusive localization of perilipin-1 on the surface of LSD Figure 1 ), it is unlikely that anti-fat IgG interfering with the normal function of perilipin-1 causes adipocyte loss. However, when live 3T3-L1 adipocytes were incubated with the antibody in the absence or presence of increasing amounts of goat serum, a dose-dependent increase in the number of labeled cells could be detected when anti-fat IgG was present Figure 4 F to Figure 4 J), but not when control IgG was used Figure 4 A to Figure 4 E). Examination of the stained cells revealed the association of anti-fat IgG with cells presenting an atypical morphology (dying or dead cells) Figure 4 J, Figure 4 N). This serum dose-dependent increase in atypical cells suggests that serum factors may cooperate with anti-fat IgG to induce cell death. This is a classic hallmark of the complement system.

[0304] Example 7: Complement activation assay.

[0305] 3T3-L1 cells were induced to differentiate under serum-free conditions in 96-well plates and allowed to accumulate lipids until day 8. The cells were then pre-incubated for 40 minutes in a total volume of 60 μl of serum-free medium without or with antibodies, and then various dilutions of rabbit complement (BAG, Lich, Germany) were added in 20 μl of serum-free medium. To terminate the reaction, 40 μl of FluoroAO / EB reagent (OneLambda, Canoga Park, USA) was added. After 15 minutes, fluorescence images were captured using a FITC filter (long-pass emission). Complement dilutions were freshly prepared and the activity was checked before each individual experiment.

[0306] Example 8: Anti-fat autoantibodies trigger complement-dependent cell death in 3T3-L1 cells.

[0307] Test whether anti-fat IgG directs complement-mediated reactions towards intact adipocytes. Complement alone or in the presence of control IgG had no effect on the staining of dead or live cells ( Figure 5 ). In contrast, within one hour, anti-fat IgG induced a substantial increase in the number of dead cells in the presence of complement ( Figure 5 A, Figure 5 B). Higher complement concentrations led to an additional increase in the number of dead cells, which was reflected by a significant loss of live cells ( Figure 5 C). In the absence of anti-fat IgG, extending the incubation time up to 24 hours did not affect cell viability or the number of dead cells, but induced an even more significant loss of live cells in the presence of anti-fat IgG ( Figure 8 ). Apparently, the low-density epitopes targeted by anti-perilipin-1 autoantibodies in the plasma membrane of adipocytes (see Figure 1 D) are sufficient to trigger complement-mediated cell death. Interestingly, after treatment with complement plus anti-fat IgG, the remaining live cell population consisted mainly of preadipocytes lacking LSDs and perilipin-1, which again indicates the necessity of perilipin-1 expression in the target cells of the anti-fat IgG-induced complement reaction.

[0308] Example 9: Anti-perilipin-1 autoantibodies trigger complement-mediated adipocyte destruction in acquired generalized lipodystrophy.

[0309] Generalized lipodystrophy is associated with severe metabolic complications. The familial type has been traced to defects in key genes of adipocyte function. The pathogenesis of acquired lipodystrophy is less understood, but it is often associated with chronic infections or autoimmune markers. Autoantibodies against adipose tissue were isolated from the sera of patients with AGL, as described in the previous examples. The immunoglobulin G fraction of patient sera, but not that of normal sera, specifically stained lipid-accumulating adipocytes in tissue sections and in vitro, indicating a direct immune response against adipocytes involved in the etiology of AGL. Lipodystrophy-associated autoantibodies react with an intracellular autoantigen that is expressed only in adipocytes, located at the surface of lipid storage droplets, and the antigen was identified as perilipin-1 by two-dimensional electrophoresis coupled with mass spectrometry. The autoantibodies do not alter cellular lipid homeostasis and do not enter intact cells. However, in the presence of serum factors or complement, the autoantibodies induce cell death in cultured adipocytes. The present invention discloses a cellular target, namely, perilipin-1, which has a key role in the selective loss of adipocytes via complement-mediated reactions in AGL.

[0310] The inventors disclose that lipodystrophy-associated autoantibodies react with an autoantigen that is expressed only in adipocytes, located at the surface of lipid storage droplets, and was identified as perilipin-1. The autoantibodies do not alter cellular lipid homeostasis and do not enter intact cells. However, in the presence of serum factors or complement, the autoantibodies induce cell death in cultured adipocytes. Anti-perilipin-1 autoantibodies are responsible for targeting the complement reaction against adipocytes.

[0311] Example 10: Antibody preparation.

[0312] A natural human antibody-phage library was used for antibody selection of perilipin-1 specific antibodies. First, non-specific or cross-reactive antibody-phages were cleared from the library (activity a). For this purpose, the library was incubated in the presence of immobilized streptavidin, magnetic streptavidin beads, and BSA. Antibody-phages that bound to the negative antigen were removed from further selection.

[0313] After that, the cleared library was screened for target antigen-specific antibodies. The following peptide antigens were used for antibody selection:

[0314] Perilipin epitope 1: NKGLTLLDGDLPEQE (SEQ ID NO: 330)

[0315] Perilipin epitope 2: QYPPEKIASELKDTI (SEQ ID NO: 331)

[0316] Perilipin epitope 5: AKPSLLSRVGALTNT (SEQ ID NO:332)

[0317] Perilipin epitope 6: EVRVPWLHSLAAAQE (SEQ ID NO:333)

[0318] Peptides were synthesized with a biotin-PEG spacer and GGSGGS linker (SEQ ID NO:438) at the N-terminus. Moreover, peptides with a biotin-PEG spacer and AAAAA linker (SEQ ID NO:439) at the C-terminus were also synthesized. The two peptide variants were purified and refined by HPLC.

[0319] First, the target peptide (with biotin at the N-terminus) was added to the clarified library preparation. Antibody-phages that bound to the biotinylated target antigen were captured and recovered from the solution using magnetic streptavidin beads. The beads were washed multiple times with BSA solution (containing 0.05% Tween 20) and PBS to remove non-specifically or weakly bound antibody-phage particles. Antigen-specific antibody-phages were eluted from the beads by trypsin treatment and rescued by E. coli infection. After short-term propagation, the bacteria were co-infected with M13K07 helper phage and antibody-phage amplification was induced. As described above, the amplified phages were used for two additional selection cycles. An overview of the antibody selection strategy is given below. The selection strategy was carried out separately for perilipin epitope 1, perilipin epitope 2, perilipin epitope 5, and perilipin epitope 6 using λ and κ antibody libraries.

[0320] Table 1: Selection strategy

[0321]

[0322]

[0323] To direct antibody-phage selection towards cell-binding antibodies, after selection cycle 2 of activity a, the antibody-phages were additionally used for selection on cells (activity b). For this purpose, the amplified phages were incubated in the presence of HEK293 cells. Antibody-phages that bound to the HEK cell surface were removed from further selection. Subsequently, the cleared antibody-phages were selected for target antigen-specific antibodies by incubation on live adipocytes. The cells were washed multiple times to remove non-specifically or weakly bound antibody-phage particles. Antigen-specific antibody-phages were rescued by E. coli infection. An overview of the antibody selection strategy is given below. Each strategy was carried out separately for λ and κ antibody-phages.

[0324] Table 2: Selection strategy

[0325]

[0326] Example 11: Antibody Screening.

[0327] After three rounds of antibody selection, the binding characteristics of monoclonal antibody clones were analyzed. First, 384 single colonies from each perilipin selection strategy (perilipin epitope 1, perilipin epitope 2, perilipin epitope 5, and perilipin epitope 6) were used for scFv antibody production (activities a and b, respectively). The binding specificities of these scFv products were tested by ELISA against the following:

[0328] Streptavidin + target peptide (N-terminal biotin);

[0329] Streptavidin + target peptide (C-terminal biotin),

[0330] Streptavidin.

[0331] An antibody clone was identified as antigen-specific if:

[0332] The signal / noise (S / N) between streptavidin + target peptide (N-terminal biotin) and streptavidin was ≥ 5, i.e., (streptavidin + target peptide (N-terminal biotin)) / (streptavidin) ≥ 5;

[0333] The S / N between streptavidin + target peptide (C-terminal biotin) and streptavidin was ≥ 5, i.e., (streptavidin + target peptide (C-terminal biotin)) / (streptavidin) ≥ 5.

[0334] A total of 827 hits were identified from activity a. A total of 146 hits were identified from activity b. Sequence analysis of these clones was performed to identify clones with unique antibody sequences (≥ one amino acid difference in the CDRs of VH and VL). The unique antibodies were as follows:

[0335] Table 3: Hits Identified in the Screening

[0336]

[0337] In activity b, 18 antibodies were identified that were also identified in parallel in activity a:

[0338] Table 4: Antibodies with Identified Unique Sequences

[0339] Strategy Antibody with unique sequence S1 (perilipin epitope 1) 8 S3 (perilipin epitope 2) 2 S9 (perilipin epitope 5) 5 S11 (perilipin epitope 6) 3 Total 18

[0340] Based on the antibody selection activities, peptide specificities, and sequence similarities, lead antibodies were selected for further testing.

[0341] Example 12: Antibody Conversion.

[0342] The VH gene and VL gene were amplified from phagemid DNA by PCR and purified. The VH gene was inserted into a mammalian human IgG1 heavy chain expression vector. The VL gene was inserted into a mammalian human IgG1 light chain λ or κ expression vector. The IgG expression vector was transformed into E. coli. Single colonies were selected for plasmid propagation. After isolating transfection-grade DNA, HEK cells were transiently co-transfected with the heavy chain and light chain expression vector DNA of an antibody clone.

[0343] Antibodies were produced by HEK cells and secreted into the culture medium for 7 days. After clearing the culture supernatant from the cells by centrifugation, the IgG antibody was purified by protein A affinity chromatography. After adjusting the buffer to PBS, the protein concentration of the antibody was determined by UV / VIS spectroscopy.

[0344] The integrity and purity of the antibody were evaluated by SDS-PAGE under reducing conditions. The functional binding activity of the antibody to the target peptide was measured by ELISA. Various antibodies were produced and their functional characteristics were tested. In particular, the binding characteristics and functional characteristics of antibodies with various VH regions and VL regions (SEQ ID NO: 334 - 437) were tested.

[0345] Example 13: Exemplary anti-perilipin-1 antibodies of the present invention.

[0346] Various antibodies of the present invention were tested in binding assays and functional assays. In particular, hIgG1 antibodies against the perilipin-1 epitope having any one of SEQ ID NO: 1 (perilipin epitope 1), SEQ ID NO: 2 (perilipin epitope 2), SEQ ID NO: 5 (perilipin epitope 5), and SEQ ID NO: 6 (perilipin epitope 6), particularly having any one of SEQ ID NO: 330, 331, 332, and 333, were tested.

[0347] Table 5: Various exemplary perilipin antibodies of the present invention and the corresponding CDR regions, VH regions, and VL regions

[0348]

[0349]

[0350]

[0351] The corresponding sequences are detailed in the sequence listing and Figure 16 (CDR-sequences) and Figure 17 (VH- and VL-sequences).

[0352] Example 14: Perilipin antibody binding assay.

[0353] Freshly isolated adipocytes from WT-untreated mice were stained with the selected antibodies. Specifically, adipocytes were isolated by collagenase digestion of adipose tissue (white adipose tissue from around the liver, intestine, kidney, and testis) from old male mice [7, 8]. Collagenase digestion was performed using a digestion buffer (Krebs-Ringers-HEPES; 2.5 mM glucose; 2% fetal bovine serum albumin; 200 μM adenosine (Sigma, 01890-5G); 1 mg / ml collagenase (Sigma, C2139), pH 7.4), where Krebs-Ringers-HEPES contained 120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl2, 10 mM HEPES, 1.2 mM KH2PO4, and 1.2 mM MgSO4. Isolated adipocytes were first blocked with a mouse FcR blocking reagent. Then, the adipocytes were incubated with the selected first antibody (anti-perilipin antibody or control) at a concentration of 1 μg / ml. As a control, to exclude non-specific binding of the antibody, an isotype control antibody (human IgG1) was used. In addition, one control sample was incubated only with the second antibody without adding the first antibody. After washing, the adipocytes were incubated with a second antibody (goat anti-human Alexa 568) that recognizes the first antibody. After incubation and another washing step, the DNA dye Hoechst 33342 was added at a 1:1000 dilution to identify intact cells in flow cytometry. Then, flow cytometry was used to analyze the binding of the anti-perilipin antibody to adipocytes.

[0354] For signal detection, an anti-human Alexa 568 that recognizes the first antibody was used ( Figure 10 and Figure 11 ). An isotype control antibody (human IgG1) was used to exclude non-specific binding of the test antibody to the cell surface, i.e., by analyzing the fluorescence intensity of the anti-perilipin antibody compared to the isotype control. The histogram of the test antibody of the present invention showed enhanced binding of the antibody of the present invention to adipocytes compared to the binding of the isotype control to adipocytes. In addition, compared to a commercially available anti-perilipin antibody, the antibody of the present invention showed enhanced binding to adipocytes ( Figure 10 and Figure 11 ).

[0355] Test the binding efficiency of various antibodies of the present invention on the surface of adipocytes. Basically according to the published protocol [9], the binding of the antibodies of the present invention was further analyzed using gold nanoparticles and electron microscopy, with modifications as described below. The differentiated adipocytes on cover slips were fixed with 4% formaldehyde and 1% glutaraldehyde in PBS at pH 7.4 for 30 minutes. Subsequently, the fixed cell layers were incubated overnight at 4 °C in the absence of the primary antibody or in the presence of 1 μg of each test antibody per cover slip. After washing, the cover slips were incubated with the bridging antibody at 4 °C for 5 hours: rabbit anti-human IgG (DAKO; catalog number A0423; for all human or humanized primary antibodies) or polyclonal mouse anti-rabbit (H+L) (Invitrogen; catalog number 31213; for the commercial rabbit anti-perilipin-1 polyclonal antibody PA1-1052 from Invitrogen). After washing, the cover slips were incubated with the gold-labeled antibody overnight at 4 °C (Britisch Biocell International; goat anti-rabbit Au-20 nm; catalog number EMGAR20; for human or humanized primary antibodies; or goat anti-mouse Au-20 nm; catalog number EMGAM20; for commercial primary antibodies). After the final wash, intact adipocytes were identified by their lipid vacuoles and microvilli, and the bound gold particles were detected in the field emission scanning electron microscopy mode.

[0356] Successful binding of the antibodies of the present invention to adipocytes was observed. The binding of an antibody of the present invention, for example antibody 5, to adipocytes is shown in Figure 15 Figure. Similar results were also observed for other antibodies of the present invention such as antibody 11, antibody 17, antibody 20, antibody 29, and antibody 31 (data not shown). In contrast, electron microscopy did not show binding of the commercial antibody Invitrogen PA1-1052 to adipocytes.

[0357] Example 15: Function assay of anti-perilipin antibodies.

[0358] The effect of anti-perilipin antibodies on complement-mediated cell death was tested in a microscopy-based cell assay. 3T3-L1 cells were differentiated into adipocytes using a serum-free differentiation protocol based on insulin [6]. Specifically, 3T3-L1 cells were incubated with a serum-free differentiation medium (SFD-medium) supplemented with insulin (1 μM), dexamethasone (0.1 μM), and 3-isobutyl-1-methylxanthine (500 μM) for 3 days. The SFD-medium consisted of DMEM / HAM’s F12 (1:1) medium at pH 7.2 with 15 mM HEPES, mixed 1:1 with DMEM (1 g / l glucose, no NaHCO3), 1.2 g / l NaHCO3, 17 μM D-pantothenic acid, 1 μM biotin, 2.0 mg / l apotransferrin, 300 mg / l fetuin, 1% penicillin / streptomycin. Cells were maintained for 4 days in SFD-medium supplemented only with insulin (1 μM). For the complement assay

[10] , cells were incubated with the selected antibodies (anti-perilipin antibodies and isotype control antibodies) at a final concentration of 0.017 mg / ml to 0.05 mg / ml in 60 μl SFD-medium (concentration of each antibody in 60 μl SFD-medium was 0.0017 mg / ml of the mixed antibodies). Commercially available lyophilized rabbit complement (BAG Diagnostics GmbH) was reconstituted in water, and then 20 μl of a 1:32 dilution of complement was added on top of the cells. After 1 hour of incubation, cells were stained with FluoroQuench TM AE and cell death was monitored using microscopy analysis.

[0359] Successful differentiation was evaluated based on cell morphological changes such as the appearance of lipid vacuoles and cell enlargement. Differentiated cells were incubated with the selected antibodies and complement. Cell death was monitored using microscopy analysis and a commercial FluoroQuench TM staining / quenching reagent from Thermo Fisher Scientific Inc.

[0360] The antibodies of the present invention showed effective complement-mediated cell death ( Figure 12 B and Figure 13 B). The functional efficacy of various antibodies of the present invention was tested and showed effective complement-mediated cell death ( Figure 12B), such as antibody 6, antibody 7, antibody 8, antibody 9, antibody 14, antibody 16, antibody 18, antibody 19, antibody 20, antibody 21, antibody 22, antibody 24, antibody 25, antibody 26, antibody 27, antibody 28, antibody 31, and antibody 32. The tested commercially available anti-perilipin antibodies did not show significant complement-mediated cell death compared to the control ( Figure 12 A, Figure 14 and Figure 15 C).

[0361] Example 16: Further evaluation of exemplary antibodies of the present invention.

[0362] The adipocyte binding efficacy of various antibodies of the present invention and their efficacy in complement-mediated cell death were further investigated (Table 6).

[0363] Table 6: Functional characterization of various antibodies (“+” indicates efficacy in at least one test, “++” indicates efficacy in at least two tests).

[0364]

[0365]

[0366] In addition, complement assays were performed with antibody pools to study the synergy of targeting several perilipin epitopes (Table 7).

[0367] Table 7: Analysis of complement-mediated cell death using antibody pools (+, ++, and +++ indicate low, medium, and high induction of complement-mediated cell death, respectively).

[0368] Antibody pool Antibody number Epitope Complement-mediated cell death 1 5-9 Perilipin epitope 1 + 2 10-11 Perilipin epitope 2 ++ 3 13-14、16-22 Perilipin epitope 5 +++ 4 23-32 Perilipin epitope 6 +++ 5 5-11 Perilipin epitopes 1 and 2 +++ 6 5-9、13-14、16-22 Perilipin epitopes 1 and 5 ++ 7 5-9、23-32 Perilipin epitopes 1 and 6 ++ 8 10-11、13-14、16-22 Perilipin epitopes 2 and 5 +++ 9 13-14、16-32 Perilipin epitopes 5 and 6 +++ 10 10-11、23-32 Perilipin epitopes 2 and 6 + 11 5-11、13-14、16-22 Perilipin epitopes 1, 2 and 5 ++ 12 5-11、23-32 Perilipin epitopes 1, 2 and 6 ++ 13 10-11、13-14、16-32 Perilipin epitopes 2, 5 and 6 ++

[0369] References

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[0371] [2] Hübler A, Abendroth K, Keiner T, W, Kauf E, Hein G et al. Dysregulation of insulin-like growth factors in a case of generalized acquired lipoatrophic diabetes mellitus (Lawrence Syndrome) connected with autoantibodies against adipocyte membranes. Exp Clin Endocrinol Diabetes, 1998;106:79 - 84.

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[0376] [7] Rodbell M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem, 1964; 239: 375-80.

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[0378] [9] Kaufmann R, Rahn S, Pollrich K, Hertel J, Dittmar Y, Hommann M, Henklein P, Biskup C, Westermann M, Hollenberg MD, Settmacher U. Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. J Cell Physiol, 2007; 211: 699-707.

[0379]

[10] Terasaki PI, McClelland JD. Microdroplet assay of human serum cytotoxins. Nature, 1964; 204: 998-1000.

[0380] The features of the present invention disclosed in the description, claims and / or drawings may be used, alone or in any combination thereof, as materials for implementing the present invention in its various forms.

Claims

1. An antigen-binding peptide that specifically binds to a perilipin-1 epitope having the following amino acid sequence: PWLHSLAA (SEQ ID NO: 6); wherein the antigen-binding peptide is an antibody or an antibody fragment, and the antibody or antibody fragment comprises i. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 114, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 115, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 116, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 117, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 118, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 119; or ii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 120, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 121, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 122, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 123, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 124, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 125; or iii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 126, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 127, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 128, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 129, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 130, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 131; or iv. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 132, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 133, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 134, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 135, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 136, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 137; or v. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:138, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:139, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:140, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:141, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:142, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:143; or vi. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:144, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:145, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:146, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:147, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:148, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:149; or vii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:150, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:151, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:152, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:153, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:154, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:155; or viii. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:156, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:157, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:159, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:160, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:161; or ix. a heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:162, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:163, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:164, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:165, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:166, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:167; or x. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 169, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 170, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 171, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 172, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 173; or xi. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 175, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 176, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 177, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 178, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 179; or xii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 210, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 211, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 212, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 213, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 214, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 215; or xiii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 216, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 217, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 218, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 219, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 220, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 221; or xiv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 222, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 223, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 224, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 225, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 226, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 227; or xv. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 228, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 229, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 230, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 231, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 232, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 233; or xvi. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 234, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 235, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 236, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 237, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 238, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 239; or xvii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 240, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 241, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 242, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 243, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 244, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 245; or xviii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 246, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 247, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 248, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 249, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 250, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 251; or xix. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 252, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 253, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 254, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 255, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 256, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 257; or xx. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 258, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 259, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 260, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 261, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 262, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 263; or xxi. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 264, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 265, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 266, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 267, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 268, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 269; or xxii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 270, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 271, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 272, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 273, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 274, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 275; or xxiii. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 276, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 277, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 278, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 279, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 280, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 281; or xxiv. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 282, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 283, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 284, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 285, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 286, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 287; or xxv. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:288, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:289, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:290, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:291, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:292, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:293; or xxvi. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:294, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:295, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:296, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:297, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:298, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:299; or xxvii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:300, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:301, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:302, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:303, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:304, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:305; or xxviii. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:306, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:307, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:308, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:309, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:310, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:311; or xxix. A heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO:312, a heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO:313, a heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO:314, a light chain CDR1 region comprising the amino acid sequence of SEQ ID NO:315, a light chain CDR2 region comprising the amino acid sequence of SEQ ID NO:316, and a light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:317; or xxx. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 318, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 319, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 320, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 321, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 322, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 323; or xxxi. The heavy chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 324, the heavy chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 325, the heavy chain CDR3 region comprising the amino acid sequence of SEQ ID NO: 326, the light chain CDR1 region comprising the amino acid sequence of SEQ ID NO: 327, the light chain CDR2 region comprising the amino acid sequence of SEQ ID NO: 328, and the light chain CDR3 region comprising the amino acid sequence of SEQ ID NO:

329.

2. The antigen-binding peptide according to claim 1, wherein the perilipin-1 epitope is a human perilipin-1 epitope.

3. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide is not an autoantibody targeting perilipin-1 in a human patient with lipodystrophy.

4. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide competes for binding with an autoantibody targeting perilipin-1 in a human patient with lipodystrophy.

5. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide binds perilipin-1 with an affinity (K -4 ) of at least 10 D M in a binding assay.

6. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide is a monoclonal antibody.

7. The antigen-binding peptide according to claim 1, which, when incubated with 3T3-L1 cells that have differentiated into adipocytes in the presence of complement, causes complement-mediated cell death of the 3T3-L1 cells and / or the differentiated adipocytes.

8. The antigen-binding peptide according to claim 1, wherein when the antigen-binding peptide is incubated with adipocytes, the antigen-binding peptide binds to the surface of the adipocytes.

9. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide is a human antibody, a humanized antibody, or a chimeric human antibody.

10. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide is a whole antibody.

11. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide is a Fab fragment, an F(ab')2 fragment, or a single-chain Fv fragment.

12. The antigen-binding peptide according to claim 1, which is capable of binding to a perilipin-1 fragment presented on adipocytes, and wherein the binding of the antigen-binding peptide to the perilipin-1 fragment on the adipocytes activates the immune effector system to target and / or eliminate the adipocytes.

13. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide comprises an Fc region.

14. The antigen-binding peptide according to claim 1, wherein the antigen-binding peptide does not cross-react with any other perilipin.

15. The antigen-binding peptide according to any one of the preceding claims, for preventing or treating obesity.

16. A bispecific antigen-binding peptide, selected from antibodies and antibody fragments, comprising: (i) a first binding site that specifically binds to a perilipin-1 epitope having SEQ ID NO: 6, the first binding site comprising a combination of heavy-chain CDR1-CDR3 and light-chain CDR1-CDR3, the combination being selected from the combinations i.-xxxi. as defined in claim 1; and (ii) a second binding site.

17. The bispecific antigen-binding peptide according to claim 16, wherein the second binding site binds to a perilipin-1 epitope having any one of LTLLDGDLPE (SEQ ID NO: 1), EKIASELK (SEQ ID NO: 2), VPIASTSDKV (SEQ ID NO: 3), PAPGHQQAQK (SEQ ID NO: 4), PSLLSRVGALTN (SEQ ID NO: 5), and PWLHSLAA (SEQ ID NO: 6), wherein the epitope is the same as or different from the epitope of the first binding site; the second binding site binds to a white adipocyte-specific surface marker; or the second binding site binds to an immune cell-specific receptor molecule.

18. The bispecific antigen-binding peptide according to claim 16 or 17, for preventing or treating obesity.

19. A composition comprising the antigen-binding peptide according to any one of claims 1 to 14 and / or the bispecific antigen-binding peptide according to any one of claims 16 to 17.

20. The composition according to claim 19, comprising more than one antigen-binding peptide according to any one of claims 1 to 14, and / or more than one bispecific antigen-binding peptide according to any one of claims 16 to 17.

21. The composition according to claim 20, wherein the composition comprises at least two or at least three or at least four or at least five or at least six bispecific antigen-binding peptides according to any one of claims 16-17, and each bispecific antigen-binding peptide among the bispecific antigen-binding peptides binds to a different perilipin-1 epitope.

22. The composition according to claim 19, used as a pharmaceutical composition for preventing or treating obesity.

23. A pharmaceutical composition comprising the antigen-binding peptide according to any one of claims 1 to 14, and / or the bispecific antigen-binding peptide according to any one of claims 16 to 17, for preventing or treating obesity.

24. An isolated nucleic acid encoding the antigen-binding peptide according to any one of claims 1 to 14, or encoding the bispecific antigen-binding peptide according to claim 16 or 17.

25. A recombinant cell comprising the nucleic acid according to claim 24.

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