KR20150001110A - Protein complex, anti-c-Met/Ang2 bispecific antibody comprising the protein complex, and method of preparation thereof - Google Patents

Abstract

The present invention relates to a protein complex including anti-biding sites for c-Met and Ang-2, dual specific antibodies for c-Met and Ang-2 obtained from the protein complex and a manufacturing method thereof. According to an embodiment of the present invention, a system for targeting c-Met and Ang-2 at the same time is built by using the protein complex.

Description

[0001] The present invention relates to a protein complex, a bispecific antibody for c-Met and Ang-2 comprising the same, and a preparation method thereof,

The present invention relates to a protein complex comprising an antigen-binding site for c-Met and an antigen-binding site for Ang-2, a bispecific antibody against c-Met and Ang-2 obtained from the protein complex, and a method for producing the same.

Monoclonal antibodies have been developed as therapeutic agents for a variety of targets as they become stronger in the new drug market. However, in many cases, they do not show satisfactory drug efficacy, or they have limitations in the development of new drugs, such as high cost of antibody production. As a method for solving these problems, since the mid 1980 's, there have been a lot of researches on double - stranded antibodies, but despite the efforts, there is no leading technology yet.

Conventional methods for producing double-stranded antibodies have difficulties in mass production of homogeneous double-stranded antibodies, or difficulties in commercialization due to low efficacy and side effects. In recent years, new antibody platforms have emerged that are competitive with the development of antibody engineering technology, but they are still in the verification stage.

In contrast, c-Met is a receptor for hepatocyte growth factor (HGF), and HGF binds to the extracellular region of c-Met receptor tyrosine kinase, resulting in cleavage, movement, morphogenesis, It is a kind of cytokine that induces the formation. c-Met is a receptor tyrosine kinase, which is a receptor tyrosine kinase that is present on the cell surface. It is a cancer-inducing gene itself. Sometimes, c-Met is involved in cancer development, cancer metastasis, cancer cell migration, cancer cell invasion, And is involved in many tumor-related mechanisms, such as the recent target of chemotherapy is a protein target.

In addition, Ang-2 is a representative substance known to be involved in angiogenesis. Angiogenesis is the mechanism by which new blood vessels are generated from existing blood vessels and is known to play an important role in organ formation, normal physiological growth, and wound healing. In addition, abnormal angiogenesis is known to play a crucial role in diseases such as tumor growth and metastasis, age-related macular degeneration, diabetic retinopathy, psoriasis, rheumatoid arthritis, and chronic inflammation.

The angiogenesis process of Ang-2 related cancer tissue is as follows. First, co-existence of cancer cells to select existing blood vessels occurs for the formation of new blood vessels in cancer tissues. Thereafter, the angiopoietin-2 pathway causes vascular degradation which destroys the function of the existing blood vessels. Due to the degeneration of existing blood vessels, the environment in the cancer tissue becomes a hypoxia environment and provides a condition in which a new blood vessel can be formed. Under these conditions, the expression of vascular endothelial cell growth factor (VEGF) is increased and new blood vessels are formed. For this reason, Ang-2 is one of the important targets in the development of angiogenesis inhibitors, and various types of angiogenesis inhibitors have been developed, and preclinical or clinical trials are actively under way.

Both c-Met and Ang-2 are increasingly important targets for the treatment of angiogenesis-related diseases, such as cancer, and a dual target that simultaneously targets c-Met and Ang-2 Development of a specific antibody is required. For this purpose, development of a technique for more effectively producing a double-specific antibody with excellent efficacy and few side effects is required.

One example provides a protein complex comprising an antigen binding site for c-Met and an antigen binding site for Ang-2.

Another example provides a method for producing the protein complex.

Another example provides a polynucleotide encoding the protein complex, a recombinant vector comprising the same, and a recombinant cell comprising the polynucleotide.

Another example provides bispecific antibodies to c-Met and Ang-2 obtained from the protein complexes.

Another example provides a method for preparing bispecific antibodies to c-Met and Ang-2 using the protein complexes.

Another example is a composition for diagnosis, prevention and / or treatment of diseases caused by activation and / or hyperactivation of c-Met and Ang-2 comprising the bispecific antibody against c-Met and Ang-2 as an active ingredient .

In the general antibody formation process, dimer formation occurs through the Fc region. In this case, since the homodimers and heterodimers are formed in a similar manner, the heterodimer formation rate, that is, the asymmetric structure Lt; RTI ID = 0.0 > antibody < / RTI > Accordingly, the present inventors have found that by combining the concept of "knob into hole" with the CH3 domain of the Fc portion of the antibody in the process of producing a double-specific antibody through single polypeptide processing, The present inventors have completed the present invention.

Accordingly, the present invention relates to a scFv-Fc bispecific antibody preparation technique with improved heterodimer formation rates.

One example provides a protein complex, wherein the protein complex comprises a first polypeptide comprising a first antigen binding site; A second polypeptide comprising a second antigen binding site; And a first linker connecting the first polypeptide and the second polypeptide.

The first antigen binding site is a single-stranded polypeptide to which a first light chain antigen binding site and / or a first heavy chain antigen binding site is linked, and may be located at the N-terminus of the first polypeptide. The second antigen binding site is a single-stranded polypeptide to which a second light chain antigen binding site and / or a second heavy chain antigen binding site is linked, and may be located at the N-terminus of the second polypeptide.

The first linker may be one which joins the C-terminus of the first polypeptide and the N-terminus of the second polypeptide. The first linker may be connected to a tag having an amino acid sequence that is cleavable within its interior, at the C-terminus of the first polypeptide, and at the N-terminus of the second polypeptide. The first linker may be, for example, a peptide linker, and the tag having the cleavable amino acid sequence may be used without particular limitation, provided that the tag includes a site which can be cleaved by an enzyme such as protease.

Specifically, the protein complex comprises a first polypeptide, a second polypeptide linked to the C-terminus of the first polypeptide, and a second polypeptide linked to the C-terminus of the first polypeptide and the N-terminus of the second polypeptide And may include a first linker.

In this specification, the term " connected to " is meant to include both a direct connection to the terminal or an indirect connection through a linker or the like.

One of the first antigen binding site of the first polypeptide and the second antigen binding site of the second polypeptide is an antigen binding site of the anti-c-Met antibody specifically recognizing c-Met as an antigen and binding specifically to c-Met And the other is the antigen binding site of the anti-Ang-2 antibody that specifically recognizes Ang-2 as an antigen. For example, in one embodiment, the first antigen binding site of the first polypeptide is an antigen binding site that specifically binds c-Met, and the second antigen binding site of the second polypeptide is specific for Ang-2 And in another embodiment, the first antigen binding site of the first polypeptide is an antigen binding site that specifically binds to Ang-2, and the second antigen binding site of the second polypeptide is and may be an antigen binding site that specifically binds c-Met.

Wherein the first antigen binding site of the first polypeptide comprises a first light chain antigen binding site or a first heavy chain antigen binding site or wherein the first light chain antigen binding site and the first heavy chain antigen binding site are linked, , ≪ / RTI > polypeptides. There is no particular limitation on the position of the first light chain antigen binding site and the first heavy chain antigen binding site or the order of connection thereof. The first light chain antigen binding site and the first heavy chain antigen binding site are in the form of a single-stranded polypeptide (single-chain variable fragment (scFv) linked via a linker (hereinafter referred to as a second linker) For example, the first polypeptide may have a form in which the C-terminus of the first light chain antigen binding site and the N-terminus of the first heavy chain antigen binding site are linked to each other through the second linker, Terminal of the first light chain antigen binding site and the N-terminal of the first light chain antigen binding site may be connected to each other through the second linker, that is, the first antigen binding site of the first polypeptide may be N- Terminal antigen binding site on the C-terminal side, a first heavy chain binding site on the N-terminal side and a first light chain antigen binding site on the C-terminal side, these And a second linker connecting the first linker and the second linker.

Also, the second antigen binding site of the second polypeptide may comprise a second light chain antigen binding site or a second heavy chain antigen binding site, or wherein the second light chain antigen binding site and the second heavy chain antigen binding site are linked, , A polypeptide (scFv). The position of the second light chain antigen binding site and the second heavy chain antigen binding site are not particularly limited, and the second light chain antigen binding site and the second heavy chain antigen binding site may be linked to each other through the third linker Can be connected. For example, in the second polypeptide, the C-terminus of the second light chain antigen binding site and the N-terminus of the second heavy chain antigen binding site are linked to each other through the third linker, or the C- And the N-terminus of the terminal and the second light chain binding site may be connected to each other through or through the third linker. That is, the second antigen binding site of the second polypeptide comprises a second light chain antigen binding site on the N-terminal side and a second heavy chain antigen binding site on the C-terminal side, or a second heavy chain antigen binding site and C -Terminus, and optionally a third linker connecting the second light chain antigen binding site and the second light chain antigen binding site.

Wherein the combination of the first light chain antigen binding site and the first heavy chain antigen binding site and the combination of the second light chain antigen binding site and the second heavy chain antigen binding site recognize c- -Met, and the other combination is a combination of a light chain antigen binding site and an Ang-2 binding site that recognizes Ang-2 as an antigen and binds specifically to Ang-2, 2 < / RTI > antibody and a heavy chain antigen binding site.

The first linker may be linked to a tag having an internally cleavable amino acid sequence at one end (e.g., at the C-terminus of the first polypeptide or at the N-terminus of the second polypeptide) or at both ends thereof , The cleavable amino acid sequence may refer to a cleavage site cleaved by an enzyme such as, for example, protease.

(For example, IgG1, IgG2, IgG3, IgG4, etc.) in the first polypeptide and the second polypeptide except for the first antigen binding site and the second antigen binding site, (For example, CH3-CH3) and / or the first antigen binding site and the second antigen binding site of the Fc region of the Fc region (e.g., IgE type, IgD type, etc.) And a hinge region connected to all or a part of the Fc region.

In one embodiment, in the protein complex, the first polypeptide and the second polypeptide have a first polypeptide and a second polypeptide dimer at the remaining sites except for the first antigen binding site and the second antigen binding site, Some modifications of the amino acid residues to form may be introduced. Such modifications may be introduced into the heavy chain constant regions of each polypeptide, e.g. the CH3 domain.

This modification can be made, for example, through the introduction of the Knob-into-hole principle. Specifically, the first polypeptide and the second polypeptide may have one or more knobs (knobs or at least one hole (s)) capable of mutually binding to the remaining sites except for the first antigen binding site and the second antigen binding site, For example, the knob may be formed in the heavy chain constant region of the polypeptide of either the first polypeptide or the second polypeptide, such as the CH3 domain, and the hole may be in the other For example, the CH3 domain of the polypeptide of SEQ ID NO: 2, and specifically, the knob and the hole may be formed at mutually corresponding positions on the CH3 domain of the respective polypeptides. The knob-hole pair included in the remaining portion of each of the second polypeptides except for each antigen-binding site is one or more It can be reassigned.

As described above, the first polypeptide and the second polypeptide may have one or more knobs or holes in the remaining part except for the first antigen binding site and the second antigen binding site, for example, the Fc site, specifically, the CH3 domain. (amino acid residues forming a hole), and through mutual bonding therebetween to form a dimer (a heterodimer). For example, the polypeptide of any one of the first polypeptide and the second polypeptide may include one or more knobs in the Fc region (e.g., the CH3 domain) and the Fc region of the other polypeptide (e.g., CH3 Domain) may include one or more holes, and they may mutually bind to form an asymmetric bispecific antibody.

In the process of forming antibodies in a cell, the Fc regions of two heavy chains are mutually bonded to form a dimer. Particularly, in the process of producing a bispecific antibody, since the probability of forming a homodimer and a heterodimer is similar, the formation rate of a bispecific antibody may be lowered by the general antibody production method described above .

The protein complex according to an example of the present invention may bind to the first polypeptide and the second polypeptide with the first antigen binding site and the second antigen binding site except for the Fc region, By forming an amino acid residue that forms one or more knobs or one or more holes that can be formed, it is possible to increase the formation rate of heterodimers by forming knob-hole bonds, thereby improving the efficiency of producing double-specific antibodies .

As used herein, the terms "knob" and "hole" refer to the site of the first polypeptide or the second polypeptide except for the antigen binding site, preferably CH3 Refers to a structure formed by the modification of an amino acid residue on a domain, which is relatively protruded (knocked) or depressed (hole) in a tertiary structure of a protein complex.

The Knob-into-hole principle is a technique for partially modifying the residues present on the contact surface between the CH3 domains of each heavy chain to increase the antibody formation rate of the desired heterodimeric form, 0.0 > CH3 < / RTI > domains. Specifically, the CH3 domain of any one of the first polypeptide and the second polypeptide comprises a residue having a relatively large (protruding) side chain than the surrounding amino acid residue, and the other CH3 domain contains a residue But may be modified to include residues having relatively small (recessed) side chains. The knob and the hole may be present at positions corresponding to each other of the CH3 domain of each of the first and second polypeptides, and there may be one or more pairs.

The knob is formed by an amino acid residue that forms a protruding structure by having a side chain relatively larger than the peripheral amino acid residue on the tertiary structure of the protein. Examples of the amino acid residue having a large side chain include, for example, Arg, Phe, Tyr, and Trp. The hole is formed by an amino acid residue forming a recessed structure by having a side chain relatively smaller than the peripheral amino acid residue in the tertiary structure of the protein. Preferably, the amino acid residue having the small side chain is Ala, Ser, Thr, Gly and Val. The amino acid residue may be selected from natural or unnatural amino acids.

The knobs and holes may be any combination of amino acids as long as the amino acid residues forming them are an amino acid pair capable of mutually bonding with each other. The pair of amino acid sequences may be, for example, Arg / Ala, Phe / Ser, Tyr / Thr or Trp / Val, but is not limited thereto.

For example, the protein complex comprises a first polypeptide, a second polypeptide, and a first linker linked to the tag, wherein the tag is attached to the C-terminus of the first polypeptide and the N-terminus of the second polypeptide, respectively One of the first polypeptide and the second polypeptide comprises an amino acid residue that forms a heavy chain constant region, such as one or more knobs in the CH3 region, and the other comprises a heavy chain constant region, such as one or more holes in the CH3 region (See Fig. 2). Or the protein complex comprises a first linker comprising a first polypeptide, a second polypeptide, and a tag, wherein the tag is attached to the N-terminus of the C-terminal or second polypeptide of the first polypeptide One of the first polypeptide and the second polypeptide comprises an amino acid residue that forms a heavy chain constant region, such as one or more knobs at the CH3 site, and the other comprises a heavy chain constant region, such as one or more holes at the CH3 site And may have a structure containing an amino acid residue (see FIG. 3)

According to one embodiment, the remaining portion except for the first antigen binding site and the second antigen binding site where the knob and the hole are located may be the CH3 domain of the Fc portion of the antibody.

The protein complex according to an exemplary embodiment of the present invention includes at least one knob and a hole that can mutually bind to each other as described above to increase the binding force between the first polypeptide and the second polypeptide to increase the formation rate of the dimer May be enhanced.

As used herein, the term "antigen binding site" is interpreted as a general term referring to a site where an antigen or an epitope binds in an immunoglobulin molecule, and the antigen binding site Lt; / RTI > may comprise a complementarity determining region (CDR). CDR refers to the amino acid sequence of the hypervariable region of the heavy and light chains of immunoglobulins. The heavy and light chains may each comprise three CDRs (CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3). The CDRs may provide the major contact residues for binding of the antibody to the antigen or epitope.

As used herein, "antigen binding site" includes the "heavy chain antigen binding site" and the "light chain antigen binding site" of an antibody. The "heavy chain antigen binding site" may include one or more selected from the group consisting of three heavy chain CDRs (CDRH1, CDRH2, and CDRH3), for example, a heavy chain variable region of an antibody. The "light chain antigen binding site" may include one or more selected from the group consisting of three light chain CDRs (CDRL1, CDRL2, and CDRL3), for example, a light chain variable region of an antibody.

The term "heavy chain" includes a variable region domain V _H comprising an amino acid sequence with a sufficient variable region sequence to confer specificity to an antigen and three constant region domains C _H1 , C _H2 and C _H3 Quot; is interpreted to mean both a full-length heavy chain and fragments thereof. The term "light chain" also encompasses both the full-length light chain comprising the variable region domain V _L and the constant region domain C _L comprising the amino acid sequence having a sufficient variable region sequence to confer specificity to the antigen and fragments thereof Is interpreted to mean inclusive.

According to one embodiment, the first polypeptide and the second polypeptide each comprise an antigen binding site in the form of single stranded Fab, single strand Fab 'or single stranded Fv (scFv) and all or a portion of the Fc (fragmented) CH3, or a portion including CH3, e.g., CH3, or CH2-CH3). The Fab has one antigen-binding site in a structure having a variable region of a light chain and a heavy chain, a constant region of a light chain, and a first constant region (C _H1 ) of a heavy chain. The Fab 'differs from Fab in that it has a hinge region that contains at least one cysteine residue at the C-terminus of the heavy chain C _H1 domain. The scFv (single-chain Fv) generally refers to a structure in which a variable region of a heavy chain and a variable region of a light chain are covalently linked or directly linked through a peptide linker.

For example, the first polypeptide and the second polypeptide may comprise a single-stranded antigen binding site (scFv) to which a light chain antigen binding site and a heavy chain antigen binding site are linked, respectively, and a single polypeptide comprising all or a portion of the Fc domain Stranded polypeptide. IgG type, IgG2, IgG3, IgG4, etc.), IgE type, IgD type and the like can be used for the rest of the first polypeptide and the second polypeptide except for the antigen binding site, , But is not limited thereto.

The first polypeptide and the second polypeptide may be those in which the antigen binding site (scFv) and the Fc domain (all or a part) are connected to each other through a hinge or not. In an embodiment, the hinge may be one having an amino acid sequence of SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103 or SEQ ID NO:

According to one embodiment, the protein complex comprises a first linker linking the first polypeptide and the second polypeptide to each other. The first linker may link the C-terminus of the first polypeptide to the N-terminus of the second light chain antigen-binding site of the second polypeptide or the N-terminus of the second heavy chain antigen binding site. The protein complex may further comprise a second linker connecting the first light chain antigen binding site and the first heavy chain antigen binding site in the first polypeptide and a second light chain binding site in the second polypeptide, And a third linker for linking.

The first linker, the second linker, and the third linker may be the same or different from each other. The peptide linker may be a variety of linkers known in the art, for example, a linker composed of a plurality of amino acids. According to one embodiment, the peptide linker may be, for example, a polypeptide consisting of 1 to 100 or 2 to 50 amino acids. The peptide linker may comprise, for example, Gly, Asn and Ser residues, and may also include neutral amino acids such as Thr and Ala. Amino acid sequences suitable for peptide linkers are known in the art. On the other hand, the linker can variably determine the length thereof without affecting the function of the fusion protein. That is, the first, second, and third linkers may each independently include 1 to 100 or 2 to 50 total of at least one member selected from the group consisting of Gly, Asn, Ser, Thr, and Ala have.

In one embodiment, the first linker is linked to a tag attached to the C-terminus of the first polypeptide, and the C-terminus of the tag attached to the C-terminus of the first polypeptide and the N-terminus of the second polypeptide -Terminus (e.g., the N-terminus of the second light chain antigen binding site or the N-terminal of the second heavy chain antigen binding site). In another embodiment, the first linker is associated with a tag attached to the N-terminus of the second polypeptide (e.g., the N-terminus of the second light chain antigen binding site or the N-terminus of the second heavy chain antigen binding site) Terminal of the first polypeptide and the N-terminal of the tag attached to the N-terminus of the second polypeptide. In another embodiment, the first linker comprises a tag attached to the C-terminus of the first polypeptide and an N-terminal of the second polypeptide (e.g., an N-terminal or a second heavy chain antigen of a second light chain antigen- Terminus of the binding site) and connecting the C-terminus of the tag attached to the first polypeptide to the N-terminus of the tag attached to the second polypeptide. The first linker is spaced a sufficient distance between the first and second polypeptides so that each polypeptide provides a distance advantageous to fold into suitable secondary and tertiary structures for proper functioning, 1 < / RTI > polypeptide and the second polypeptide are not separated from each other by a predetermined distance or more, thereby increasing the possibility of linking these two, and lowering the possibility of forming an undesired isomic dimer, Type protein complex can be obtained at a high efficiency.

According to one embodiment, the first linker may be connected to the tag at the end of at least one of the inner and / or the distal ends. For example, the tag may be linked to the C-terminus of the first polypeptide, the N-terminus of the second polypeptide, or both, and may comprise at least one terminal or internally cleavable amino acid sequence. In the case of a tag that binds to the N-terminus of the second polypeptide, it may be bound to the N-terminus of the light chain antigen binding site or to the N-terminus of the heavy chain antigen binding site.

As used herein, the term "tag" refers to a protein or polypeptide that is bound to the end of the linker and mediates between the different polypeptides, , The tag may be linked to the N-terminus and / or the C-terminus of the first polypeptide and / or the second polypeptide.

According to one embodiment, the tag may comprise an amino acid sequence that is cleavage in vitro or in vivo. The cleavage in vitro or in vivo may be by protease. According to one embodiment, the tag may be at least one selected from the group consisting of ubiquitin, ubiquitin-like protein, TEV cleavage peptide, and furin cleavage peptide, but is not limited thereto .

The TEV protease cleavage site may be Glu-Asn-Leu-Tyr-Phe-Gln- (Gly / Ser), wherein the cleavage occurs between Gln- (Gly / Ser). The furin protease cleavage site may be Arg-X- (Arg / Lys) -Arg (where X is any amino acid), wherein the cleavage site immediately after the target sequence is cleaved.

Ubiquitin (Ub) (Gene Accession No .: NP_001170884, NM_001177413) is the most conserved protein found in nature and consists of 76 amino acid sequences and is the perfect homology between evolutionary species such as insects, trout and humans It is a visible water-soluble protein. In addition, ubiquitin is known to be stable to changes in pH, not easily denatured at high temperatures, and stable to proteases. It is also a very safe protein that does not show any toxicity or side effects in the body. Thus, ubiquitin can improve the insolubility of the protein complex and can be safely and easily cleaved in vitro or in vivo.

The ubiquitin-like protein is a protein having similar characteristics to ubiquitin, for example, Nedd8 (NP_006147.1, NM_006156.1), SUMO-1 (NP_001005781.1, NM_001005781), SUMO-2 (NP_008868.3, NM_006937 UB5 (NP_001041706.1, NM_001048241.2), ISG15 (NP_005092.1, NM_005101. 3), and the like, but the present invention is not limited thereto.

The ubiquitin-like protein may be selected from the group consisting of wild-type ubiquitin, wild-type ubiquitin-like protein, mutant ubiquitin and mutant ubiquitin-like protein.

The mutant ubiquitin means that the amino acid sequence of the wild type ubiquitin is changed to another amino acid sequence. For example, the mutant ubiquitin may include ubiquitin in which Lys of wild type ubiquitin is substituted with Arg. According to one embodiment, in the mutant ubiquitin in which the Lys of the wild-type ubiquitin is substituted with Arg, the substitution is carried out in at least one of Lys present at 6th, 11th, 27th, 29th, 33th, 48th and 63rd positions of the wild type ubiquitin And substitution can be made independently or in combination at the position of the Lys. . Therefore, the mutant ubiquitin is preferably a mutant ubiquitin, wherein at least one of the Lys residues at positions 6, 11, 27, 29, 33, 48 and 63 in the amino acid sequence of wild type ubiquitin (Gene Accession No .: NP_001170884, NM_001177413) , Ala, Ile, Leu, Met, Phe, Pro, Trp, Val, Asn, Cys, Gln, Gly, Ser, Thr, Tyr, Asp, Glu, Arg and His. ). ≪ / RTI >

According to one embodiment, the ubiquitin or ubiquitin-like protein may comprise an amino acid sequence cleavable by the protease at the C-terminus for cleavage in vitro or in vivo. Amino acid sequences cleavable by the protease can be identified through a search database known in the art. For example, the protease that is searched at http://www.expasy.org/tools/peptidecutter/peptidecutter_enzymes.html and its cleavable amino acid sequence can be used. When the cleavable amino acid sequence is included, the protein complex may be a protein complex in which two or more fusion proteins have double or multispecific antigen binding sites by cleaving the tag contained in the protein complex in in vitro or in vivo. You can do that.

As described above, one of the first antigen binding site and the second antigen binding site is an antigen binding site of an anti-c-Met antibody recognizing c-Met protein as an antigen, and the other is an antigen binding site of Ang-2 Lt; RTI ID = 0.0 > Ang-2 < / RTI > The antigen binding site is a region involved in recognition and binding of an antigen in the antibody structure, and includes a complementarity determining region (CDR) of the antibody, a variable region including CDR, scFv, (scFv) ₂ , Fab, Fab 'or F ') ₂ , and the like.

"c-Met" or "c-Met protein" means a receptor tyrosine kinase that binds hepatocyte growth factor. The c-Met protein may be derived from any species and may be derived from primates such as human c-Met (e.g., NP_000236), monkey c-Met (e.g., Macaca mulatta, NP_001162100) Derived from rodents such as Met (e.g., NP_032617.2), rat c-Met (e.g., NP_113705.1), and the like. Such a protein includes, for example, a polypeptide encoded by a nucleotide sequence provided in GenBank Aceession Number NM_000245, or a protein encoded by a polypeptide sequence provided in GenBank Aceession Number NP_000236, or an extracellular domain thereof. The receptor tyrosine kinase c-Met is involved in various mechanisms such as, for example, cancer development, cancer metastasis, cancer cell migration, cancer cell infiltration, and neovascularization process.

An anti-c-Met antibody that recognizes c-Met as an antigen and provides an antigen-binding site that specifically binds to c-Met may be one that recognizes a specific site in c-Met, such as a specific site in the SEMA domain, as an epitope , and all antibodies or antigen-binding fragments thereof that act on c-Met to induce cellular internalization and degradation.

C-Met, a receptor for HGF (Hepatocyte growth factor), is divided into three parts: the extracellular site, the transmembrane site, and the intracellular site. In the extracellular site, the? -Subunit and the? -Subunit The HGF binding domain, the SEMA domain, the PSI domain (plexin-semaphorins-integrin homology domain), and the IPT domain (immunoglobulin-like fold shared by plexins and transcriptional factors domain). The SEMA domain of the c-Met protein may be the one having the amino acid sequence of SEQ ID NO: 79, which is a domain present in the extracellular domain of c-Met and corresponds to the site to which HGF binds. A region having an amino acid sequence of SEQ ID NO: 71 corresponding to a specific site in the SEMA domain, for example, 106th to 124th, is a loop between the No. 2 and No. 3 propeller domains in the epitope within the SEMA domain of the c- , And can act as an epitope of the anti-c-Met antibody proposed in the present invention.

An epitope is an antigenic determinant, which is interpreted to mean a portion of the antigen recognized by the antibody. According to one embodiment, the epitope is located at a site comprising at least five contiguous amino acids in the SEMA domain (SEQ ID NO: 79) of the c-Met protein, such as at position 106 in the SEMA domain of the c- To SEQ ID NO: 71 corresponding to SEQ ID NO: 71 to SEQ ID NO: 71. For example, the epitope may consist of 5 to 19 consecutive amino acids including SEQ ID NO: 73 (EEPSQ) in the amino acid sequence of SEQ ID NO: 71, for example, an amino acid sequence of SEQ ID NO: 71, SEQ ID NO: 72 or SEQ ID NO: ≪ / RTI >

The epitope having the amino acid sequence of SEQ ID NO: 72 corresponds to the outermost position of the loop region between the domains 2 and 3 of the propeller structure in the SEMA domain of the c-Met protein, and the amino acid sequence of SEQ ID NO: Is an antibody or antigen binding fragment according to one embodiment most specifically binds to a site.

Thus, the anti-c-Met antibody may specifically bind to an epitope comprising 5 to 19 consecutive amino acids comprising SEQ ID NO: 73 (EEPSQ) of the amino acid sequence of SEQ ID NO: 71, 71, SEQ ID NO: 72, or SEQ ID NO: 73, or an antigen-binding fragment that specifically binds to an epitope having the amino acid sequence of SEQ ID NO:

According to one embodiment, the antigen binding site of the anti-c-Met antibody (an antigen binding site that specifically binds c-Met)

A CDR-H1 having the amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 2, or a sequence of 8 to 19 consecutive amino acids including the third to tenth amino acids in the amino acid sequence of SEQ ID NO: CDR-H2 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 85, or SEQ ID NO: 85, and consecutive 6 to 13 amino acids including the first to sixth amino acids in the amino acid sequence of SEQ ID NO: A heavy chain antigen binding site comprising an amino acid sequence of at least one heavy chain complementarity determining region (CDR) selected from the group consisting of CDR-H3 having an amino acid sequence consisting of amino acid residues; And

CDR-L1 having the amino acid sequence of SEQ ID NO: 7, CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and amino acid sequence of SEQ ID NO: 9, SEQ ID NO: 86, or SEQ ID NO: A light chain antigen binding site comprising an amino acid sequence of at least one light chain complementarity determining region selected from the group consisting of CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids including up to the 9th amino acid

Lt; / RTI >

SEQ ID NO: 4 to SEQ ID NO: 9 may be the amino acid sequence represented by the following general formula I to VI:

General Formula I

Xaa ₁ -Xaa ₂ -Tyr-Tyr-Met-Ser (SEQ ID NO: 4),

General formula II

Arg-Asn-Xaa ₃ -Xaa ₄ -Asn-Gly-Xaa _5- Thr (SEQ ID NO: 5)

General formula III

Asp-Asn-Trp-Leu-Xaa ₆ -Tyr (SEQ ID NO: 6),

The general formula IV

_{Lys-Ser-Ser-Xaa 7} -Ser-Leu-Leu-Ala-Xaa 8 -Gly-Asn-Xaa 9 -Xaa 10 -Asn-Tyr-Leu-Ala ( SEQ ID NO: 7)

Formula V

Trp-Xaa ₁₁ -Ser-Xaa ₁₂ -Arg-Val-Xaa ₁₃ (SEQ ID NO: 8)

The general formula VI

Xaa ₁₄ -Gln-Ser-Tyr-Ser-Xaa ₁₅ -Pro-Xaa _16- Thr (SEQ ID NO: 9)

Wherein Xaa ₁ is absent or Pro or Ser, Xaa ₂ is Glu or Asp,

Xaa ₃ is Asn or Lys, Xaa ₄ is Ala or Val, Xaa ₅ is Asn or Thr,

In the above general formula (III), Xaa ₆ is Ser or Thr,

Xaa ₇ is He, Arg, Gln or Lys, Xaa ₈ is Ser or Trp, Xaa ₉ is His or Gln, Xaa ₁₀ is Lys or Asn,

Xaa ₁₁ is Ala or Gly, Xaa ₁₂ is Thr or Lys, Xaa ₁₃ is Ser or Pro,

Wherein Xaa ₁₄ is Gly, Ala or Gln, Xaa ₁₅ is Arg, His, Ser, Ala, Gly or Lys and Xaa ₁₆ is Leu, Tyr, Phe or Met.

In one embodiment, the CDR-H1 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: The CDR-H2 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 25, and SEQ ID NO: 26. The CDR-H3 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO:

The CDR-L1 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: The CDR-L2 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: The CDR-L3 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 13, 14, 15, 16, 37, 88,

In one embodiment, the antigen binding portion of the anti-c-Met antibody comprises a polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, (CDR-H2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 25, and SEQ ID NO: 26 and an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: A heavy chain antigen binding site comprising a polypeptide having a sequence (CDR-H3); (CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: (CDR-L2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, and a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: (CDR-L3) having an amino acid sequence selected from the group consisting of SEQ ID NO: 37, SEQ ID NO: 86, and SEQ ID NO: 89.

According to one embodiment, the antigen-binding portion of the anti-c-Met antibody comprises an amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 74, SEQ ID NO: 87, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 75, SEQ ID NO: 88, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, A light chain variable region (light chain antigen binding site) comprising the amino acid sequence of SEQ ID NO: 98, SEQ ID NO: 99 or SEQ ID NO: 107. In one embodiment, the antigen binding site of the anti-c-Met antibody may comprise the amino acid sequence of SEQ ID NO: 113.

On the other hand, Ang-1, Ang-2, Ang-3 and Ang-4 are known in angiopoietin, among which Ang-2 is also known as ANGPT2 and is expressed in the vascular remodeling site. In the present invention, another antigen binding site may be an antigen binding site of an anti-Ang-2 antibody that recognizes Ang-2 as an antigen. The recognizable Ang-2 may be of human origin, for example, NCBI Accession No. 2. NP_001138.1, NP_001112359.1, NP_001112360.1, or the like.

The antigen binding site of the anti-Ang-2 antibody may comprise a heavy chain variable region (heavy chain binding site) of SEQ ID NO: 109 and a light chain variable region (light chain antigen binding site) of SEQ ID NO: 110. For example, the antigen binding site of the anti-Ang-2 antibody may have the amino acid sequence of SEQ ID NO: 121.

In another example, the antigen binding site of an anti-Ang-2 antibody is

A polypeptide having the amino acid sequence of SEQ ID NO: 131 (CDR-H1), a polypeptide having the amino acid sequence of SEQ ID NO: 132 (CDR-H2), and a polypeptide having the amino acid sequence of SEQ ID NOs: 156 to 163 A heavy chain antigen binding site comprising at least one selected from the group consisting of: And / or

(CDR-L2) having the amino acid sequence of SEQ ID NO: 134 and a polypeptide (CDR-L3) having the amino acid sequence of SEQ ID NO: 135. The polypeptide having the amino acid sequence of SEQ ID NO: Lt; RTI ID = 0.0 > a < / RTI > light chain antigen binding site

: ≪ / RTI >

X1-Y-X2-M-S (SEQ ID NO: 131)

X3-I-X4-X5-X6-X7-X8-X9-X10-Y-Y-A-

X11-G-S-S-N-I-G-X12-N-X13-V-X14 (SEQ ID NO: 133)

X15-X16-X17-X18-R-P-S (SEQ ID NO: 134)

X19-X20-W-D-X21-S-L-X22-X23 (SEQ ID NO: 135)

In SEQ ID NO: 131,

(D), serine (S), or asparagine (N) such as aspartic acid (D) or asparagine (N)

X2 is alanine (A), aspartic acid (D), or tyrosine (Y)

In the above SEQ ID NO: 132,

X3 is alanine (A), glycine (G), leucine (L) or serine (S), for example alanine (A), glycine (G)

X4 is tyrosine (Y) or serine (S)

X5 is proline (P), histidine (H), or serine (S)

X6 is aspartic acid (D), glycine (G), or serine (S)

X7 is serine (S), glycine (G), or aspartic acid (D)

X8 is glycine (G) or serine (S)

X9 is asparagine (N) or serine (S)

X10 is lysine (K), isoleucine (I), threonine (T)

In the above SEQ ID NO: 133,

X11 is serine (S) or threonine (T)

X12 is asparagine (N) or serine (S)

X13 is alanine (A), tyrosine (Y), aspartic acid (D)

X14 is asparagine (N), serine (S), threonine (T), tyrosine (Y)

In SEQ ID NO: 134,

X15 is alanine (A), or serine (S)

X16 is an aspartic acid (D) or asparagine (N)

X17 is serine (S) or asparagine (N), such as serine (S)

X18 is asparagine (N), lysine (K), histidine (H), or glutamine (Q)

In SEQ ID NO: 135,

X19 is glycine (G) or alanine (A)

X20 is serine (S), alanine (A), or threonine (T), such as serine (S) or threonine (T)

X21 is tyrosine (Y), or aspartic acid (D) such as tyrosine (Y)

X22 is serine (S) or asparagine (N), such as serine (S)

X23 is glycine (G) or alanine (A).

For example, the antigen-binding site of the anti-Ang-2 antibody comprises a polypeptide (CDR-H1) having an amino acid sequence selected from SEQ ID NOs: 140 to 147, a polypeptide having an amino acid sequence selected from SEQ ID NOS: 148 to 155 (CDR- , And a polypeptide having an amino acid sequence selected from SEQ ID NOS: 156 to 163 (CDR-H3), and a heavy chain antigen binding site comprising at least one selected from the group consisting of: (CDR-Ll) having an amino acid sequence selected from SEQ ID NOS: 164 to 171, a polypeptide (CDR-L2) having an amino acid sequence selected from SEQ ID NOS: 172 to 179, And a light chain antigen binding site comprising at least one selected from the group consisting of a polypeptide having a sequence (CDR-L3).

For example, the antigen-binding site of the anti-Ang-2 antibody is selected from the group consisting of SEQ ID NOS: 196 to 203, wherein the heavy chain binding site and / or the light chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 188 to 195 Lt; RTI ID = 0.0 > amino acid < / RTI > sequence.

The sequence of the antigen binding site of the anti-Ang-2 antibody is summarized in the following Tables 1 to 3:

Heavy chain CDR CDRH1-KABAT CDRH2-KABAT CDRH3-KABAT DYAMS
(SEQ ID NO: 140) AIYPDSGNKYYADSVKG
(SEQ ID NO: 148) ARHSSDPKVKSGYYDDGMDV
(SEQ ID NO: 156) DYYMS
(SEQ ID NO: 141) GIYPSGGSTYYADSVKG
(SEQ ID NO: 149) ARDPSTLTYAGFDY
(SEQ ID NO: 157) NYAMS
(SEQ ID NO: 142) AISSGGGNIYYADSVKG
(SEQ ID NO: 150) AKSGIQPSPPSMSSAYAMDV
(SEQ ID NO: 158) DYAMS
(SEQ ID NO: 143) SIYPDDGNTYYADSVKG
(SEQ ID NO: 151) ARHTSHHTSIDGYYYYGMDG
(SEQ ID NO: 159) DYDMS
(SEQ ID NO: 144) SISHGDSNKYYADSVKG
(SEQ ID NO: 152) AKSSGIQESPPTYYYYGMDV
(SEQ ID NO: 160) DYAMS
(SEQ ID NO: 145) SIYPDDGNTYYADSVKG
(SEQ ID NO: 153) AKHPVRLNLHPMYYYYGMDV
(SEQ ID NO: 161) SYDMS
(SEQ ID NO: 146) LISPDSSSIYYADSVKG
(SEQ ID NO: 154) AKDLISFWRGGFDY
(SEQ ID NO: 162) DYDMS
(SEQ ID NO: 147) GISSDDGNTYYADSVKG
(SEQ ID NO: 155) ARPTIDKYTLRGYYSYGMDV
(SEQ ID NO: 163)

Light chain CDR CDRL1-KABAT CDRL2-KABAT CDRL3-KABAT SGSSSNIGNNAVN
(SEQ ID NO: 164) ADSNRPS
(SEQ ID NO: 172) GSWDYSLSG
(SEQ ID NO: 180) SGSSSNIGNNYVT
(SEQ ID NO: 165) ADSHRPS
(SEQ ID NO: 173) ATWDYSLSG
(SEQ ID NO: 181) SGSSSNIGNNDVY
(SEQ ID NO: 166) ANSHRPS
(SEQ ID NO: 174) GTWDYSLSG
(SEQ ID NO: 182) TGSSSNIGNNDVS
(SEQ ID NO: 167) SDSKRPS
(SEQ ID NO: 175) GSWDYSLSG
(SEQ ID NO: 183) SGSSSNIGSNAVN
(SEQ ID NO: 168) ADSNRPS
(SEQ ID NO: 176) GSWDYSLSG
(SEQ ID NO: 184) TGSSSNIGNNAVS
(SEQ ID NO: 169) SDSQRPS
(SEQ ID NO: 177) ATWDYSLSA
(SEQ ID NO: 185) SGSSSNIGSNYVN
(SEQ ID NO: 170) SDSHRPS
(SEQ ID NO: 178) GAWDDSLSG
(SEQ ID NO: 186) TGSSSNIGSNYVS
(SEQ ID NO: 171) SDNKRPS
(SEQ ID NO: 179) GTWDDSLNG
(SEQ ID NO: 187)

Heavy chain antigen binding site Light chain antigen binding site EVQLLESGGGLVQTGGSLRLSCAASGFTFS DYAMS WVRQAPGKGLEWVS AIYPDSGNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARHSSDPKVKSGYYDDGMDV WGQGTLVAVSS (SEQ ID NO: 188) QSVLTQPPSASGTPGQRVTISC SGSSSNIGNNAVN WYQQLPGTAPKLLIY ADSNRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GSWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 196) EVQLLESGGGLVQPGGSLRLSCAASGFTFS DYYMS WVRQAPGKGLEWVS GIYPSGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARDPSTLTYAGFDY WGQGTLVTVSS (SEQ ID NO: 189) QSVLTQPPSASGTPGQRVTISC SGSSSNIGNNYVT WYQQLPGTAPKLLIY ADSHRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC ATWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 197) EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS AISSGGGNIYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKSGIQPSPPSMSSAYAMDV WGQGTLVTVSS (SEQ ID NO: 190) QSVLTQPPSASGTPGQRVTISC SGSSSNIGNNDVY WYQQLPGTAPKLLIY ANSHRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GTWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 198) EVQLLESGGGLVQPGGSLRLSCAASGFTFS DYAMS WVRQAPGKGLEWVS SIYPDDGNTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARHTSHHTSIDGYYYYGMDG WGQGTLVTVSS (SEQ ID NO: 191) QSVLTQPPSASGTPGQRVTISC TGSSSNIGNNDVS WYQQLPGTAPKLLIY SDSKRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GSWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 199) EVQLLESGGGLVQPGGSLRLSCAASGFTFS DYDMS WVRQAPGKGLEWVS SISHGDSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKSSGIQESPPTYYYGMDV WGQGTLVTVSS (SEQ ID NO: 192) QSVLTQPPSASGTPGQRVTISC SGSSSNIGSNAVN WYQQLPGTAPKLLIY ADSNRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GSWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 200) EVQLLESGGGLVQTGGSLRLSCAASGFTFS DYAMS WVRQAPGKGLEWVS SIYPDDGNTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKHPVRLNLHPMYYYYGMD VWGQGTLVTVSS (SEQ ID NO: 193) QSVLTQPPSASGTPGQRVTISC TGSSSNIGNNAVS WYQQLPGTAPKLLIY SDSQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC ATWDYSLSA YVFGGGTKLTVLG (SEQ ID NO: 201) EVQLLESGGGLVQPGGSLRLSCAASGFTFS SYDMS WVRQAPGKGLEWVS LISPDSSSIYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC AKDLISFWRGGFDY WGQGTLVTVSS (SEQ ID NO: 194) QSVLTQPPSASGTPGQRVTISC SGSSSNIGSNYVN WYQQLPGTAPKLLIY ADSNRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GSWDYSLSG YVFGGGTKLTVLG (SEQ ID NO: 202) EVQLLESGGGLVQPGGSLRLSCAASGFTFS DYDMS WVRQAPGKGLEWVS GISSDDGNTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYC ARPTIDKYTLRGYYSYGMDV WGQGTLVTVSS (SEQ ID NO: 195) QSVLTQPPSASGTPGQRVTISC TGSSSNIGSNYVS WYQQLPGTAPKLLIY SDNKRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC GTWDDSLNG YVFGGGTKLTVLG (SEQ ID NO: 203)

In another example, the antigen binding site of an anti-Ang-2 antibody is

A polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 204 to SEQ ID NO: 207, a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 208 to 211, (CDR-H3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 212 to 215; a heavy chain antigen binding site comprising at least one selected from the group consisting of: And / or

(CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 to 219, a polypeptide having the amino acid sequence of SEQ ID NO: 136 (CDR-L2) Peptide (CDR-L3), which comprises at least one light chain antigen binding site

: ≪ / RTI >

X ₁ -X ₂ -SX ₃ -X ₄ -X ₅ -X ₆ (SEQ ID NO: 136)

QQX ₇ -X ₈ -X ₉ -X ₁₀ -PX ₁₁ -T (SEQ ID NO: 137)

In SEQ ID NO: 136,

X ₁ is arginine (R) or tyrosine (Y)

X ₂ is alanine (A) or threonine (T)

X ₃ is asparagine (N), arginine (R), or serine (S)

X ₄ is leucine (L) or arginine (R)

X ₅ is an aspartic acid (D), histidine (H), or tyrosine (Y)

X ₆ is serine (S) or proline (P)

In the above SEQ ID NO: 137,

X ₇ is serine (S), glycine (G), aspartic acid (D) or tyrosine (Y)

X ₈ is asparagine (N), tyrosine (Y), or serine (S)

X ₉ is glutamic acid (E), threonine (T), or lysine (K)

X ₁₀ is an aspartic acid (D), serine (S), or leucine (L)

X ₁₁ is leucine (L), tryptophan (W), or tyrosine (Y).

For example, the antigen-binding site of the anti-Ang-2 antibody comprises a polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 204 to SEQ ID NO: 207, an amino acid sequence selected from the group consisting of SEQ ID NO: (CDR-H3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 212 to 215, and a heavy chain antigen binding region comprising at least one selected from the group consisting of: (CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 to 219, a polypeptide (CDR-L2) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 220 to 223, And a polypeptide (CDR-L3) having an amino acid sequence selected from the group consisting of SEQ ID NO: 224 to SEQ ID NO: 227 In may be one containing the light chain antigen-binding site comprising one or more selected.

For example, the antigen binding site of the anti-Ang-2 antibody may comprise a heavy chain antigen binding site having an amino acid sequence selected from the group consisting of SEQ ID NOs: 228 to 231, and / or a light chain antigen having an amino acid sequence selected from the group consisting of SEQ ID NOS: 232 to 235 Binding site.

The sequences of the antigen binding sites of the above anti-Ang-2 antibodies are summarized in Tables 4 to 6 below:

Heavy chain CDR CDRH1-KABAT CDRH2-KABAT CDRH3-KABAT SYWLE
(SEQ ID NO: 204) EILPGSGSTNYNEKFRG
(SEQ ID NO: 208) GNHNSYYYAMDY
(SEQ ID NO: 212) DPYIH
(SEQ ID NO: 205) RIDPANGNTKYDPKFQG
(SEQ ID NO: 209) RWDGGGFDY
(SEQ ID NO: 213) DYYMK
(SEQ ID NO: 206) EINPKNGDTFYNQIFKG
(SEQ ID NO: 210) ENDYDVGFFDY
(SEQ ID NO: 214) NYGMN
(SEQ ID NO: 207) WINTYTGEPTYADDFKG
(SEQ ID NO: 211) DHDGYLMDY
(SEQ ID NO: 215)

Light chain CDR CDRL1-KABAT CDRL2-KABAT CDRL3-KABAT RASESVDSYGNSFMH (SEQ ID NO: 216) RASNLDS (SEQ ID NO: 220) QQSNEDPLT (SEQ ID NO: 224) RASQDISNYLN (SEQ ID NO: 217) YTSRLHS
(SEQ ID NO: 221) QQGNTLPWT (SEQ ID NO: 225) KASQSVSNDVA (SEQ ID NO: 218) YASNRYP (SEQ ID NO: 222) QQDYTSPWT (SEQ ID NO: 226) STSQGISNYLN
(SEQ ID NO: 219) YTSSLHS
(SEQ ID NO: 223) QQYSKLPYT
(SEQ ID NO: 227)

Heavy chain antigen binding site Light chain antigen binding site QVQLQQSGAELMKPGASVKISCKATDYTFSS
YWLEWLIQRPGHGLEWIGEILPGSGSTNYNE
KFRGKATFTEDTSSNTAYMQLSSLTSEDSAV
YYCARGNHNSYYYAMDYWGQGTSVTVSS (SEQ ID NO: 228) DIVLTQSPASLAVSLGQRATISCRASESVDSY
GNSFMHWYQQKPGQPPKLLIYRASNLDSGIPAR
FSGSGSRTDFTLTINPVEADDVATYYCQQSNED
PLTFGAGTKLELK (SEQ ID NO: 232) EVQLQQSGAELVKPGASVKLSCTASGFNIKDPY
IHWVKQRPEQGLEWIGRIDPANGNTKYDPKFQG
KATITADTSSNTAYLQLSSLTSEDTAVYYCVRR
WDGGGFDYWGQGTSVTVSS (SEQ ID NO: 229) DIQMTQTTSSLSASLGDRVTISCRASQDISNY
LNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGS
GSGTDYSLTITNLEQEDIATYFCQQGNTLPWTF
GGGTKLEIK (SEQ ID NO: 233) EVQLQQSGPELVKPGDSVKMSCKASGYTFTDYYM
KWVRQSHGKSLQWVGEINPKNGDTFYNQIFKGKA
TLTVDKSSSTAYMQLTSLTSEDSAVYYCTRENDY
DVGFFDYWGQGTSVTVSS (SEQ ID NO: 230) TIVMTQTPKFLLVSAGDRITITCKASQSVSNDV
AWYQQKPGQSPKLLIYYASNRYPGVPDRFTGSG
YGTDFTFTISTVQAEDLAVYFCQQDYTSPWTFG
GGTELEIK (SEQ ID NO: 234) QIQLVQSGPELKKPGETVKISCKASGYTFTNYG
MNWVKQAPGKGLKWMGWINTYTGEPTYADDFKG
RFAFSLETSASTAYLQINNLKNEDTATYFCARD
HDGYLMDYWGQGTSVTVSS (SEQ ID NO: 231) DIQMTQTTSSLSASLGDRVTISCSTSQGISNYL
NWYQQKPDGTVKLLIFYTSSLHSGVPSRFSGSG
SGTDYSLTISNLEPEDIATYYCQQYSKLPYTFG
GGTKLEIK (SEQ ID NO: 235)

In another example, the antigen binding site of an anti-Ang-2 antibody is

A polypeptide having the amino acid sequence of SEQ ID NO: 236 (CDR-H1), a polypeptide having the amino acid sequence of SEQ ID NO: 138 (CDR-H2), and a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 240 to SEQ ID NO: Peptide (CDR-H3); a heavy chain antigen binding site comprising at least one selected from the group consisting of peptides (CDR-H3); And / or

A polypeptide having the amino acid sequence of SEQ ID NO: 243 or SEQ ID NO: 244 (CDR-L1), a polypeptide having the amino acid sequence of SEQ ID NO: 245 or SEQ ID NO: 246 (CDR- Peptide (CDR-L3), which comprises at least one light chain antigen binding site

: ≪ / RTI >

YIX ₁ -YX ₂ -GX ₃ -TX ₄ -YNPSLKS (SEQ ID NO: 138)

QQDYX ₅ -SPX ₆ -T (SEQ ID NO: 139)

In the general formula 1,

X ₁ is serine (S) or asparagine (N)

X ₂ is serine (S) or arginine (R)

X ₃ is serine (S) or asparagine (N)

X ₄ is serine (S) or aspartic acid (D)

In the general formula 2,

X ₅ is a serine (S), threonine (T), or arginine (R),

X ₆ is proline (P), lysine (L), or tryptophan (W).

(CDR-H1) having the amino acid sequence of SEQ ID NO: 236, a polypeptide (CDR-H2) having the amino acid sequence selected from the group consisting of SEQ ID NOS: 237 to 239, , And a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOS: 240 to 242 (CDR-H3), and / or an amino acid sequence of SEQ ID NO: 243 or 244 (CDR-Ll), a polypeptide having the amino acid sequence of SEQ ID NO: 245 or 246 (CDR-L2), and a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NOs: 247 to 251 -L3). ≪ / RTI >

For example, the antigen-binding site of the anti-Ang-2 antibody is selected from the group consisting of a heavy chain antigen binding site comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 252 to SEQ ID NO: 256 and / or a group consisting of SEQ ID NO: Lt; RTI ID = 0.0 > amino acid < / RTI > sequence.

The sequences of the antigen binding sites of the above anti-Ang-2 antibodies are summarized in Tables 7 to 9 below:

Heavy chain CDR sequence CDRH1-KABAT CDRH2-KABAT CDRH3-KABAT DYAWN
(SEQ ID NO: 236) YISYSGSTSYNPSLKS
(SEQ ID NO: 237) STFGHYVSSMDY
(SEQ ID NO: 240) DYAWN
(SEQ ID NO: 236) YINYRGNTDYNPSLKS
(SEQ ID NO: 238) GNFEGAMDY
(SEQ ID NO: 241) DYAWN
(SEQ ID NO: 236) YISYSGSTSYNPSLKS
(SEQ ID NO: 237) GDYGNYVGPMDY
(SEQ ID NO: 242) DYAWN
(SEQ ID NO: 236) YINYSGNTDYNPSLKS
(SEQ ID NO: 239) GNFEGAMDY
(SEQ ID NO: 241)

Light chain CDR amino acid sequence CDRL1-KABAT CDRL2-KABAT CDRL3-KABAT KASQSASNDVA
(SEQ ID NO: 243) YASNRYT
(SEQ ID NO: 245) QQDYSSPPT
(SEQ ID NO: 247) KASQSVSNDVA
(SEQ ID NO: 244) YASNRYP
(SEQ ID NO: 246) QQDYTSPWT
(SEQ ID NO: 248) KASQSVSNDVA
(SEQ ID NO: 244) YASNRYT
(SEQ ID NO: 245) QQDYSSPLT
(SEQ ID NO: 249) KASQSVSNDVA
(SEQ ID NO: 244) YASNRYP
(SEQ ID NO: 246) QQDYRSPWT
(SEQ ID NO: 250) KASQSVSNDVA
(SEQ ID NO: 244) YASNRYP
(SEQ ID NO: 246) QQDYSSPWT
(SEQ ID NO: 251)

Heavy chain antigen binding site Light chain antigen binding site VQLQESGPGLVKPSQSLSLTCTVTGYSITS DYAWN WIRQFPGNKLEWMG YISYSGSTSYNPSLKS RISITRDTSKNQFFLQLNSVTPEDTATYYCAR STFGHYVSSMDY WGQ (SEQ ID NO: 252) SIVMTQTPKLLLVSAGDRVTITCKASQSASNDVAWYQQKPGQSPKLLIYYASNRYTGVPDRFTGSGYGTDFTFAISTVQAEDLAIYFCQQDYSSPPTFGGGTKLEIK (SEQ ID NO: 257) VQLQESGPGLVKPSQSLSLSCTVTGYSIAS DYAWN WIRQFPGNKVEWMG YINYRGNTDYNPSLKS RSSINRDTSKNQFFLQLNSVTTGDTATYYCAR GNFEGAMDY WGQ (SEQ ID NO: 253) TIVMTQTPKFLLVSAGDRITITC KASQSVSNDVA WYQQKPGQSPKLLIY YASNRYP GVPDRFTGSGYGTDFTFTISTVQAEDLAVYFC QQDYTSPWT FGGGTELEIK (SEQ ID NO: 258) LQLQESGPGLVKPSQSLSLTCTVTGYSITS DYAWN WIRQFPGNKLEWMG YISYSGSTSYNPSLKS RISITRDTSKNQFFLQLNSLTTEDTATYYCAR GDYGNYVGPMDY WGQ (SEQ ID NO: 254) SIVMTQTPKFLLVSAGDRVTITC KASQSVSNDVA WYRQKPGQSPKLLIY YASNRYT GVPDRFTGSGYGTDFTFTISTVQAEDLAVYFC QQDYSSPLT FGARTKLELK (SEQ ID NO: 259) VQLQESGPGLVKPSQSLSLTCTVTGYSITS DYAWN WIRQFPGNKLEWMG YINYSGNTDYNPSLKS RSSITRNTSKNQFFLQLNSVTTGDTATYYCTR GNFEGAMDY W (SEQ ID NO: 255) SIVMTQTPKFLLVSAGDRVTITC KASQSVSNDVA WYQQKPGQSPKLLIY YASNRYP GVPDRFTGSGYGTDFTFTISTVQAEDLAVYFC QQDYRSPWT FGGGTKLEIK (SEQ ID NO: 260) VQLQESGPGLVKPSQSLSLTCTVTGYSITS DYAWN WIRQFPGNKLEWMG YINYSGNTDYNPSLKS RSSITRDTSKNQFFLQLNSVTTGDTATYYCAR GNFEGAMDY WG (SEQ ID NO: 256) SIVMTQTPKFLLVSAGDRVTITC KASQSVSNDVA WYQQKPGQSPKLLIY YASNRYP GVPDRFTGSGYGTDFTFTISTVQAEDLAVYFC QQDYSSPWT FGGGTKLEIK (SEQ ID NO: 261)

According to one embodiment, the polypeptide comprises a first polypeptide, a second polypeptide, a first linker linking the first polypeptide and the second polypeptide, and a second linker connecting the N-terminus, the C- Which is located in the "

One of the first polypeptide and the second polypeptide may comprise a heavy chain variable region (heavy chain antigen binding site), a light chain variable region (light chain antigen binding site), a heavy chain variable region and a light chain variable region A linker connecting the variable region, a hinge of a human antibody, and an Fc region of a human antibody,

The other is a heavy chain variable region (heavy chain antigen binding site), a light chain variable region (light chain antigen binding site), a linker connecting the heavy chain variable region and the light chain variable region, A hinge, and an Fc region of a human antibody,

And a first linker connecting the C-terminus of the first polypeptide to the N-terminus of the second polypeptide and being connected to the tag.

According to one embodiment, the polypeptide comprises an amino acid sequence of SEQ ID NO: 127 (a polypeptide which does not include Knob-into-hole; the first to 19th amino acid sequences are secretory signal sequences) The amino acid sequence of SEQ ID NO: 129 (the polypeptide comprising Knob-into-hole, the first to the 19th secretory signal sequence), the 20th to 1066th amino acids of SEQ ID NO: 129 Or a polypeptide having an amino acid sequence selected from the group consisting of amino acid sequences.

The protein complex is a single-stranded polypeptide having a double-specific (specificity to two antigens) linked to a tag and a linker, and can serve as an antibody precursor protein that can be produced as a bispecific antibody through cleavage of a tag have.

Thus, another example provides bispecific antibodies to c-Met and Ang-2 comprising the protein complexes described above. The bispecific antibody may be one wherein the protein complex itself or the first and second polypeptides of the protein complex are dimerized and / or the cleavage site of the tag is cleaved to have a complete antibody form. For example, when the protein complex comprises one tag, the bispecific antibody may be a cleavage site of the tag, and the protein complex may include two tags (first tag And the second tag), the cut portion of the two tags is cut so that the first tag, the second tag, or the form in which the first tag and the second tag are connected to each other is removed from the first linker or the first linker end .

Since the bispecific antibody has different antigen binding sites (an antigen binding site specifically binding to c-Met or an antigen binding site specifically binding to Ang-2) in each monomer, c-Met and Ang- 2 can be recognized as targets at the same time.

According to one embodiment, the bispecific antibody may be a mouse-derived antibody, a mouse-human chimeric antibody, or a humanized antibody.

The bispecific antibody may be F (ab ') 2, (scFv) 2, Diabody, Di-scFv, nanobody, or IgG type.

When the animal-derived antibody is subjected to a chimerization process, the animal-derived IgG1 hinge is replaced with a human IgG1 hinge. However, the animal-derived IgG1 hinge is shorter in length than the human IgG1 hinge, and the disulfide bond disulfide bond decreases from 3 to 2, and the rigidity of the hinge is different from each other. Thus, modification of the hinge region can increase the antigen binding efficiency of the humanized antibody. Methods of deletion, addition, or substitution of amino acids to modify the amino acid sequence of the hinge region are well known to those skilled in the art.

Another example is a pharmaceutical composition for preventing and / or treating diseases related to the activation and / or hyperactivation of c-Met and Ang-2 comprising the bispecific antibody against c-Met and Ang-2 as an active ingredient do.

 In another example, a therapeutically effective amount of a bispecific antibody to c-Met and Ang-2 is administered to a subject in need of prevention and / or treatment of a disease associated with the activation and / or hyperactivation of c-Met and Ang-2 There is provided a method of preventing and / or treating diseases associated with the activation and / or hyperactivation of c-Met and Ang-2, comprising the step of administering to a patient. The method of preventing and / or treating further comprises identifying a patient in need of prevention and / or treatment of a disease associated with activation and / or over-production of c-Met and Ang-2 prior to the administration step .

The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, which is usually used for the formulation of drugs, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate , Alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. , But the present invention is not limited thereto. The pharmaceutical composition may further comprise at least one member selected from the group consisting of a diluent, an excipient, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent,

The pharmaceutical composition may be administered orally or parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration and intrathecal administration. When administered orally, the protein or peptide is extinguished and the oral composition should be formulated to coat the active agent or protect it from degradation from above. In addition, the composition may be administered by any device capable of transferring the active agent to the target cell.

The content of the bispecific antibody against c-Met and Ang-2 in the pharmaceutical composition may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration interval, administration route, And responsiveness. ≪ / RTI > For example, the daily dose of the bispecific antibody to c-Met and Ang-2 may range from 0.001 to 1000 mg / kg, specifically from 0.01 to 100 mg / kg, more specifically from 0.1 to 50 mg / kg But is not limited thereto. The daily dose may be formulated into a single dosage form in unit dose form, formulated in an appropriate amount, or intruded into a multi-dose container.

The pharmaceutical composition may be in the form of solutions, suspensions, syrups or emulsions in an oil or aqueous medium, or may be formulated in the form of excipients, powders, granules, tablets or capsules, May additionally include topics.

In particular, the pharmaceutical compositions comprising bispecific antibodies to c-Met and Ang-2 can be formulated as immuno-liposomes, since they include antibodies. Liposomes containing antibodies can be prepared according to methods well known in the art. The immunoliposome is a lipid composition comprising phosphatidylcholine, cholesterol and polyethylene glycol-derivatized phosphatidylethanolamine and can be prepared by reverse phase evaporation. For example, a Fab 'fragment of an antibody can be conjugated to a liposome via a disulfide-replacement reaction.

Meanwhile, the bispecific antibody to c-Met and Ang-2 specifically binds to c-Met and Ang-2, and thus it is confirmed whether or not c-Met and Ang-2 are activated and / or overexpressed . Thus, another example of the invention is the use of c-Met and Ang-2 activation and / or over-production and / or c-Met and Ang-2 activation comprising a bispecific antibody to c-Met and Ang- / RTI > and / or < RTI ID = 0.0 > and / or < / RTI > In another example, treating a biopsy sample obtained from a patient with a bispecific antibody for c-Met and Ang-2; Confirming whether an antigen-antibody reaction has occurred; And an antigen-antibody response is detected, the patient is judged to have c-Met and Ang-2 activation and / or over-production symptoms or have c-Met and Ang-2 activation and / or over-production related diseases The method comprising the steps of: The biological sample may be selected from the group consisting of cells, tissues, body fluids and the like obtained from the patient.

The step of confirming whether the antigen-antibody reaction is confirmed can be carried out through various methods known in the art. For example, it can be measured by a conventional enzyme reaction, fluorescence, luminescence and / or radiation detection, and specifically, immunochromatography, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescence immunoassay (FIA), luminescence immunoassay (LIA), Western blotting ), And the like, but the present invention is not limited thereto.

The subject to be administered or diagnosed with the pharmaceutical composition may be a mammal including primates including humans, monkeys and the like, rodents including mice, rats and the like.

The diseases associated with c-Met and Ang-2 activation and / or hyperproliferation include, but are not limited to, cancer, metastasis, retinopathy of prematurity, macular degeneration (e.g., age-related macular degeneration), diabetic retinopathy, angiogenic glaucoma, Asthma, psoriasis, rheumatoid arthritis, chronic inflammation, hypertension, arteriosclerosis, sepsis. The cancer may be overexpressing c-Met and Ang-2, and may be solid tumors, including but not limited to squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, Cancer, endometrioid cancer, pituitary cancer, soft tissue sarcoma, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, Pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer, colon cancer, endometrial or uterine cancer, salivary cancer, renal cancer, prostate cancer, mucin cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma May be at least one selected from the group consisting of

Another example provides a polynucleotide encoding the protein complex described above.

The term "polynucleotide" is a polymer of a deoxyribonucleotide or a ribonucleotide present in single-stranded or double-stranded form. RNA genomic sequences, DNA (gDNA and cDNA), and RNA sequences transcribed therefrom, and include analogs of natural polynucleotides unless otherwise specified.

The polynucleotide includes not only a nucleotide sequence encoding the amino acid sequence of the protein complex but also a sequence complementary to the sequence. The complementary sequence includes a perfectly complementary sequence as well as a substantially complementary sequence that is capable of hybridizing under stringent conditions known in the art to the nucleotide sequence of the nucleotide sequence encoding the amino acid sequence of the protein complex ≪ RTI ID = 0.0 > and / or < / RTI >

In addition, the nucleotide sequence encoding the amino acid sequence of the protein complex may be modified. Such modifications include addition, deletion or non-conservative substitution or conservative substitution of nucleotides. The polynucleotide encoding the amino acid sequence of the protein complex is also interpreted to include a nucleotide sequence that exhibits substantial identity to the nucleotide sequence. The above substantial identity is determined by aligning the nucleotide sequence with any other sequence as much as possible and analyzing the aligned sequence using algorithms commonly used in the art to obtain a sequence having at least 80% homology, At least 90% homology or at least 95% homology.

According to one embodiment, the polynucleotide comprises a nucleotide sequence of SEQ ID NO: 128, wherein the first to 57th amino acid residues are the secretory signal sequence coding region, the 3199th to the 3201st codon are stop codons, the 60th nucleotide of SEQ ID NO: 128 The nucleotide sequence of SEQ ID NO: 130 (the first to the 57th is the secretory signal sequence coding region, the 3199th to 3201th is the termination codon), and the 60th to 3198th nucleotides of SEQ ID NO: 130 A nucleotide sequence selected from the group consisting of SEQ ID NOs.

Yet another example provides a recombinant vector (expression vector) comprising a polynucleotide encoding said protein complex and an expression regulator (e. G., A promoter, etc.) operatively linked to said polynucleotide.

The term "vector" means means for expressing a gene of interest in a host cell. For example, viral vectors such as plasmid vectors, cosmid vectors and bacteriophage vectors, adenovirus vectors, retroviral vectors, and adeno-associated viral vectors. The vector that can be used as the recombinant vector may be a plasmid (for example, pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8 / 9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14 , pGEX series, pET series and pUC19), phage (e.g.,? gt4? B,? -charon,?? z1 and M13) or viruses (e.g., SV40 and the like).

The polynucleotide encoding the protein complex in the recombinant vector may be operatively linked to a promoter. The term "operatively linked" refers to the functional linkage between a nucleotide expression control regulatory sequence (e.g., a promoter sequence) and another nucleotide sequence. The regulatory sequence may be "operatively linked" to regulate transcription and / or translation of other nucleotide sequences.

The recombinant vector can typically be constructed as a vector for cloning or as a vector for expression. The expression vector may be any conventional vector used in the art to express an exogenous protein in plants, animals or microorganisms. The recombinant vector may be constructed by a variety of methods known in the art.

The recombinant vector may be constructed with prokaryotic or eukaryotic cells as hosts. For example, when the vector to be used is an expression vector and the prokaryotic cell is used as a host, a strong promoter capable of promoting transcription (for example, pL [ ^lambda] promoter, CMV promoter, trp promoter, lac promoter, tac promoter, T7 promoter, etc.), a ribosome binding site for initiation of translation and a transcription / translation termination sequence. When a eukaryotic cell is used as a host, the origin of replication that functions in eukaryotic cells contained in the vector includes f1 replication origin, SV40 replication origin, pMB1 replication origin, adeno replication origin, AAV replication origin, and BBV replication origin But is not limited thereto. Also, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or mammalian viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, The cytomegalovirus promoter and HSV tk Promoter) can be used, and generally has a polyadenylation sequence as a transcription termination sequence.

Another example provides a recombinant cell comprising said recombinant vector.

The recombinant cell may be obtained by introducing the recombinant vector into an appropriate host cell. The host cell may be any host cell known in the art as a cell capable of continuously cloning or expressing the recombinant vector stably. Examples of the prokaryotic cell include E. coli JM109, E. coli Bacillus subtilis, Bacillus subtilis, and Bacillus strains such as E. coli RR1, E. coli LE392, E. coli B, E. coli X1776, E. coli W3110, Bacillus subtilis, and Salmonella typhimurium, Yeast ( Saccharomyce cerevisiae ), insect cells, plant cells and animal cells, for example, Sp2 / 0 (yeast), yeast But are not limited to, CHO (Chinese hamster ovary) K1, CHO DG44, PER.C6, W138, BHK, COS-7, 293, HepG2, Huh7, 3T3, RIN and MDCK cell lines.

The delivery (introduction) of the polynucleotide or the recombinant vector containing the polynucleotide into a host cell can be carried out by a method well known in the art. For example, when the host cell is a prokaryotic cell, the CaCl ₂ method or the electroporation method can be used. When the host cell is a eukaryotic cell, the microinjection method, the calcium phosphate precipitation method, the electroporation method, Liposome-mediated transfection methods, and gene bombardment, but the present invention is not limited thereto.

The method of selecting the transformed host cells can be easily carried out according to a method widely known in the art by using a phenotype expressed by a selection marker. For example, when the selection mark is a specific antibiotic resistance gene, the transformant can be easily selected by culturing the transformant in a medium containing the antibiotic.

Another example provides a method for producing a bispecific antibody comprising the step of expressing the recombinant vector to produce the protein complex.

The method for producing the bispecific antibody can be performed in vivo or ex vivo.

When the bispecific antibody is produced in vivo, when the recombinant vector is expressed in the cell to produce a protein complex, the protein complex may be released into the cell in the form of a complete bispecific antibody in the cell. That is, after the protein complex is translated in an endoplasmic reticulum, the first polypeptide and the second polypeptide are positioned adjacent to each other through a linker to spontaneously form a dimer to form a protein complex can do. Thereafter, the cleavable amino acid sequence present in the tag is cleaved by the protease present in the cell, so that a complete type of double-specific antibody can be produced. At this time, due to one or more amino acid sequences (knock domain and hole domain) mutually binding to each other except for the first antigen binding site and the second antigen binding site present in the first polypeptide and the second polypeptide, The formation rate of the bispecific antibody can be further increased. Thereafter, the produced bispecific antibody can be purified and used according to a purification method well known in the art.

In the case where the bispecific antibody is produced ex vivo, the step of producing the protein complex by expressing the recombinant vector in a cell may further comprise the step of cleaving the tag.

In vitro, the protein complex is present in a state where the first polypeptide and the second polypeptide are linked by a linker, and the first polypeptide and the second polypeptide may form a dimer spontaneously adjacent to each other. At this time, due to one or more amino acid sequences (knock domain and hole domain) mutually binding to each other except for the first antigen binding site and the second antigen binding site present in the first polypeptide and the second polypeptide, The formation rate of the dimer can be further increased.

According to one embodiment, the step of cleaving the tag may be by the addition of a protease recognizing the cleavable amino acid sequence contained in the tag of the protein complex. In addition, the tag may be selected from the group consisting of ubiquitin, ubiquitin-like protein, TEV cleavage peptide and purine cleavage peptide, but is not limited thereto. For example, the tag may comprise a ubiquitin, a ubiquitin-like protein, a TEV cleavage peptide, or a purine cleavage peptide by adding to the protein complex a protease capable of cleaving the ubiquitin, ubiquitin- The cleaved peptide is cleaved and cleaved by a protease, so that a bispecific antibody can be produced from the protein complex.

The step of cutting such a tag can be performed before or after the dimer formation.

By using the protein complex according to one embodiment, it is possible to effectively construct a double-specific antibody system that simultaneously targets two antigens or two epitopes. Therefore, Lt; / RTI >

FIGS. 1 to 3 are schematic views showing a method of producing a protein complex and a bispecific antibody comprising a first polypeptide and a second polypeptide according to an embodiment,
Figure 1 illustrates the preparation of a bispecific antibody using single-stranded polypeptides and tags,
Figure 2 illustrates the preparation of a bispecific antibody using a single-stranded polypeptide, a first tag, a second tag, and a knob-hole,
Figure 3 illustrates the preparation of bispecific antibodies using single-stranded polypeptides, tags, and knob-holes.
FIG. 4 schematically shows a DNA sequence to be inserted into an expression vector for preparing a protein complex according to an embodiment.
FIG. 5A shows SDS-PAGE results of the bispecific antibody produced from the protein complex according to one embodiment, and FIG. 5b shows the absorbance at 280 nm of the bispecific antibody obtained by ion-exchange chromatography.
Figure 6 shows the affinity for the c-Met of single specific scFv-Fc antibodies used in the design of bispecific antibodies according to one embodiment.
Figure 7 shows the affinity for Ang2 of monospecific scFv-Fc antibodies used in the design of bispecific antibodies according to one embodiment.
8a is a graph showing c-Met degradation activity of a bispecific antibody produced from a protein complex according to an embodiment, and 8b is a graph showing the degree of Akt phosphorylation of a bispecific antibody produced from a protein complex according to an embodiment .
9 is a graph showing the degree of phosphorylation of the Tie2 receptor of a bispecific antibody produced from a protein complex according to one embodiment.

Hereinafter, one or more embodiments will be described in more detail by way of examples. However, these embodiments are intended to illustrate one or more embodiments, and the scope of the present invention is not limited to these embodiments.

Figures 1 to 3 are schematic diagrams of a protein complex comprising a first polypeptide comprising a first antigen binding site and a second polypeptide comprising a second antigen binding site according to one embodiment.

Figure 1 shows a first polypeptide comprising a first antigen binding site (red: comprising a first light chain antigen binding site and a first heavy chain antigen binding site) and a second antigen binding site (blue: second light chain antigen binding site And a second polypeptide comprising a second heavy chain antigen binding site, a tag bound to the C-terminus of the first polypeptide (yellow), and a N-terminal of the C-terminus of the tag and the N polypeptide of the second polypeptide (Left and right) containing a linker connecting the ends of the tag, and a complete form of the bispecific antibody (right) in which the cleavable site of the tag is truncated.

As illustrated in Figure 2, a second polypeptide 200 comprising a first polypeptide 100 comprising first antigen binding sites 101 and 102 and a second antigen binding site 201 and 202, The first tag 302 and the second tag 303 are connected to the ends of the linker 300 and the first tag 302 and the second tag 303 are connected to the end of the linker 300 composed of the polypeptide have. Since the first tag 302 and the second tag 303 are composed of a protein such as ubiquitin or ubiquitin-like protein, it is possible to cleave in-vitro or in-vivo. A first polypeptide 100 comprising the first antigen binding sites 101 and 102 and a second polypeptide 200 comprising the second antigen binding sites 201 and 202 on in vitro or in vivo A knob 400 formed in the CH3 domain of the first polypeptide 100 and a hole 500 formed in the CH3 domain of the second polypeptide 200 ) Are mutually linked, so that the formation rate of a bispecific protein complex having different antigen binding sites can be further increased.

FIG. 3 is a schematic diagram of a protein complex comprising a first polypeptide comprising a first antigen binding site and a second polypeptide comprising a second antigen binding site according to one embodiment disclosed in FIG. 2, An example of the form is shown. As described above, through the in vitro or in vivo cleavage of the protein complex, a biospecific protein complex having different antigen binding sites is formed. However, the protein complex disclosed in FIG. Terminal of the second light chain antigen binding site 201 or the second heavy chain antigen binding site 202 of the second polypeptide 200 comprising the second antigen binding sites 201 and 202 does not have a linker Since the linker 300 comprises 2 to 50 short amino acid sequences, the second polypeptide 200 comprising the second antigen-binding sites 201 and 202 may have a short amino acid sequence, It does not affect the function.

Example  1: Preparation of an expression vector of a protein complex containing two different antigen binding sites

To prepare a precursor protein complex of a bispecific antibody comprising specific binding sites for cMet and Ang2, the expression vector of the protein complex was prepared by commissioning Genotech. The vector for overexpression of the protein was pCEP4 (Invitrogen) Respectively.

Specifically, as shown in Fig. 4 (A), a secretory signal sequence (ss) (amino acid sequence: SEQ ID NO: 111, DNA sequence: SEQ ID NO: 112), c-Met binding site (amino acid sequence: (Amino acid sequence: SEQ ID NO: 121, DNA: SEQ ID NO: 114) and a hinge, amino acid sequence: SEQ ID NO: 115, DNA sequence: SEQ ID NO: (Amino acid sequence: SEQ ID NO: 117, DNA sequence: SEQ ID NO: 118) composed of the Fc domain (amino acid sequence: SEQ ID NO: 115, DNA sequence: SEQ ID NO: 116) and the ubiquitin tag Single-stranded DNA (SEQ ID NO: 128) encoding the amino acid sequence (SEQ ID NO: 127) of the protein complex composed of the GS linker was synthesized and inserted into pCEP4 (Invitrogen) to prepare a protein complex expression vector.

As shown in FIG. 4 (B), a secretory signal sequence (ss) (amino acid sequence: SEQ ID NO: 111, DNA sequence: SEQ ID NO: 112), c-Met binding site (amino acid sequence: A single chain polypeptide consisting of an Fc domain (amino acid sequence: SEQ ID NO: 123, DNA sequence: SEQ ID NO: 124) including an amino acid sequence including a hinge and forming a knob, (Amino acid sequence: SEQ ID NO: 125, DNA sequence: SEQ ID NO: 126) containing an Ang2 binding site (amino acid sequence: SEQ ID NO: 121, DNA sequence: SEQ ID NO: 122) (SEQ ID NO: 130) encoding the amino acid sequence (SEQ ID NO: 129) of the protein complex composed of the ubiquitin tag (amino acid sequence: SEQ ID NO: 117, DNA sequence: SEQ ID NO: 118) and GS linker ) Was synthesized and inserted into pCEP4 (Invitrogen) to prepare a protein complex expression vector.

The nucleotide sequence (aagctt) which can be cleaved with HindIII at the 5 'end of the inserted DNA fragment was inserted into the HindIII-Xho1 truncation sequence of the pCEP4 vector by inserting a nucleotide sequence (ctcgag) Respectively.

Example  2: Expression of protein complex and purification of bispecific antibody

Human embryonic kidney cells (HEK293-F, Korean Cell Line Bank) transformed with the vector were used to over-express the protein complex using the vector prepared in Example 1 above. HEK293-F cells were maintained in an orbital shaker at 130 rpm at 37 ° C and 8% CO ₂ . For transformation, cells were first separated from the culture medium by centrifugation, 1 x 10 ⁶ cells were suspended in Freestyle 293 Expression media (Invitrogen), and 100 ug of the vector (Invitrogen) using FreeStyle ^™ MAX reagent ) Was used to transform the above HEK293-F cells. The supernatant was collected by centrifugation (4000 xg, 10 min, 4 ° C) 7 to 8 days after the transformation and filtered using a pore size 0.22 micron filter. The supernatant thus obtained was used for the purification of the protein complex. Protein complexes were separated using Protein A affinity column (GE Healthcare). First, Protein A affinity column was equilibrated with 1X PBS (Invitrogen) solution. The supernatant was applied to Protein A affinity column equilibrated with the solution, and then washed with washing buffer (1X PBS) corresponding to 5 times the column volume And the protein complex was eluted with elution buffer (IgG elution buffer, Thermo Scientific) containing 10% glycerol. The eluted solution was immediately neutralized with 1 M Tris-HCl (pH 9.0) solution. The eluate from the Protein A affinity column was again applied to a Mono S column (GE Healthcare) equilibrated with equilibrium solution (30 mM MES (pH 5.0)). Proteins not bound to the column were removed through the application of the equilibrium solution, and the proteins bound to the column were washed slowly with a washing solution consisting of 25 mM MES and salt (NaCl) from 150 mM to 300 mM Followed by elution. The protein complex-containing fractions were confirmed by absorbance at 280 nm (FIG. 5b) and SDS-PAGE using non-reducing gel (FIG. 5a). As a result, as shown in FIGS. 5A and 5B, heterodimer formation of the antibody having the cMet binding site, the hinge-Fc and the ubiquitin, and the antibody having the Ang2 binding site and the hinge-Fc was confirmed.

Example  3: Antigen-Antibody Affinity  Identification and measurement

In order to measure the binding affinity of the antigen-antibody reaction of the monospecific antibody used in the design of the bispecific antibody, a surface plasmon resonance experiment was performed using a BiacoreT100 instrument (GE healthcare) Respectively. 1X HBS-EP (GE healthcare) was used as the running buffer and dilution buffer. The prepared bispecific antibody was immobilized on the surface of a CM5 chip (GE healthcare) at about 5000 RU (response unit) using a standard amine-coupling reaction. A single specific antibody or anti-human FC antibody (GE healthcare) was immobilized on the bottom of the chip and the antigen (c-MET or Ang2; RnD systems) was flowed at various concentrations (6.25-100 nM) at a rate of 10 μL / min gave. The association phase was 180 seconds and the separation time (washing with running buffer) was 600 seconds. After each coupling cycle, the bound antigen and antibody were removed from the chip by flowing the regeneration solution, Glycine-HCl pH 2.0 (GE healthcare) at a rate of 50 μL / min for 1 minute. The resulting sensorgram was fitted with a 1: 1 Langmuir binding model in the BIA evaluation software. The results are shown in Fig. 6 and Fig.

Example  4: Antibodies produced from a protein complex anti - cMet efficacy Wow agonistic effect

The low side effects and efficacy of the bispecific antibodies presented in the present invention on c-Met were verified by a mechanism-based experiment.

The c-MET binding portion of the bispecific antibody was demonstrated by measuring the total amount of c-Met for c-Met degradation efficacy. Since it is already known that the binding of c-Met and HGF promotes the growth of cancer cells, it has been proved that when the total amount of c-Met is decreased by the antibody treatment, the growth of cancer cells is also lowered, and thus the anticancer activity of the antibody can be verified .

The human total HGF R / c-Met ELISA kit (R & D) was prepared by mixing 2X10 ⁵ cells / ml of the MKN45 gastric cancer cell line (JCRB0254, Shinjuku, Japan) with ⁵ ug / ml of each antibody for 24 hours (RPMI medium, GIBCO) ELISA experiments were performed using the ELISA system. Finally, Super Aquablue (eBiosciences) was added to react and the colorimetric signals were measured at the OD value at 450 nm. The measured values for each antibody were converted to relative values for the control (media only, 100%) without antibody treatment, and are shown in FIG. 8A. M in FIG. 8A is an anti-c-Met scFv-Fc antibody comprising the anti-c-Met antibody (c-Met binding site (SEQ ID NO: 113) and Fc Anti-Ang2 scFv-Fc antibody having an amino acid sequence encoded by SEQ ID NO: 2), MxN means the bispecific antibody prepared in Example 2 above.

As shown in Fig. 8 (a), the bispecific antibody showed better c-Met decomposition efficiency than the untreated control group.

The degree of phosphorylation of AKT was quantitatively measured by ELISA method in order to examine the safety of the antibody. Cell function regulated by AKT includes cell proliferation, cell survival, cell size regulation, responsiveness to available nutrients, intermediate metabolism, angiogenesis, and tissue invasion. All of these processes are characteristic of cancer cells, and many oncoproteins and tumor suppressors interact with each other on the AKT pathway. In the connection between signal transduction and classical metabolic control, In order to control the temperature of the liquid. Therefore, the higher the degree of AKT phosphorylation and activation, the higher the tumor forming ability. Therefore, the anti-cancer effect of the antibody was tested by measuring the degree of inhibition of phosphorylation of AKT by the antibody treatment.

The AKT phosphorylation site was Ser473 and the AKT phosphorylation was measured using the PathScan phospho-AKT1 (Ser473) chemiluminescent sandwich ELISA kit (Cell signaling).

One day before the test, the Caki-1 kidney cancer cell line (HTB-46; ATCC, Manassas, VA) cultured at 2 × 10 ⁵ cells / ml was treated with ⁵ ug / ml antibody in serum-free DMEM medium for 30 minutes And then tested using the above ELISA kit.

The obtained results were measured with a Perkins Elmer machine. The degree of phosphorylation of AKT of the antibody was determined as a relative value based on the degree of phosphorylation by 5D5 used as a positive control (100%).

The results obtained are shown in Fig. 8B. As shown in Figure 8B, the double antibody was isolated from ATCC Cat. # HB-11895 hibroblastoma cells obtained from the American Type Culture Collection (ATCC, Manassas, Va.) As a positive control 5D5 ), The effect of inhibiting AKT phosphorylation was remarkably high.

Example  5: Antibodies produced from protein complexes Tie -2 phosphorylation efficacy

The degree of phosphorylation of Tie2 receptor binding to Ang2 was quantitated to confirm Ang2 inhibition of dual antibodies. Ang2 binds to the Tie2 receptor of vascular endothelial cells and transmits signals. This affects the growth and activity of vascular endothelial cells, thus contributing to angiogenesis which can contribute to cancer cell growth. Thus, by measuring the phosphorylation of Tie2, the efficacy of dual antibodies can be confirmed.

Double antibody was treated with 2.5 × 10 ⁵ cells / ml and 5% FBS v / v IMDM (Invitrogen) in CHO (Chinese hamster ovary) cells transfected with Tie2 overexpression (Kim et al., Biochim Bioohys Acta . Of Tie2 was detected by phosphor-tyrosine (4G10, Millipore) antibody.

More specifically, ^five 2.5X10 CHO cells overexpressing Tie2 receptor were cultured in IMDM medium supplemented with 5% (v / v) FBS at 37 ° C in a 60-mm culture dish and 80-90% confluency , And serum-free IMDM medium for 16 hours at 37 ° C. After washing once with PBS, the medium was changed to IMDM medium mixed with 0.1 nM sodium orthovanadate and further cultured for 10 minutes. After washing once with PBS, the antibody N (Ang2 antibody; anti-Ang2 scFv-Fc antibody having an amino acid sequence encoded by SEQ ID NO: 262) described in Example 4 and the antibody MxN Specific antibodies) were mixed with 20 nM of Ang-2 protein (R & D systems) for 20 minutes, treated with the cultured cells, and further cultured for 10 minutes.

The cells were washed with cold PBS and treated with 300 μl of lysis buffer (Roche). The cells were collected in a tube, dissolved at 4 ° C for 30 minutes, and centrifuged at 13,000 rpm for 15 minutes. Respectively. (2 μg / ml) was added to a 96-well plate coated with an anti-Tie-2 antibody (R & D system) for 2 hours and reacted with HRP-conjugated-phospho tyrosine antibody (Millipore) for 2 hours . Measure the value on a plate reader using a substrate capable of color development.

The results obtained are shown in Fig. As shown in FIG. 9, it can be confirmed that the treatment of the bispecific antibody also reduces the phosphorylation of Tie2 to the extent equivalent to that of the anti-Ang2 antibody treatment. This is the result that the anti-c-Met / Ang2 bispecific antibody of the present invention maintains the Tie2 inhibitory ability of anti-Ang2 alone antibody equally or more.

100: first polypeptide
101: first light chain antigen binding site
102: first heavy chain antigen binding site
200: second polypeptide
201: second light chain antigen binding site
202: second heavy chain antigen binding site
300: first linker
301: Tag
302: first tag
303: Second tag
400: knob
500: hole

<110> Samsung Electronics Co. Ltd <120> Protein complex, anti-c-Met / Ang2 bispecific antibody          the protein complex, and the method of preparation thereof <130> DPP20124522KR <160> 262 <170> Kopatentin 1.71 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR1 of AbF46 <400> 1 Asp Tyr Tyr Met Ser   1 5 <210> 2 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR2 of AbF46 <400> 2 Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala Ser   1 5 10 15 Val Lys Gly             <210> 3 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of AbF46 <400> 3 Asp Asn Trp Phe Ala Tyr   1 5 <210> 4 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR1 of c-Met antibody <220> <221> UNSURE <222> (1) <223> X is Pro or Ser or absent <220> <221> UNSURE <222> (2) <223> X is Glu or Asp <400> 4 Xaa Xaa Tyr Tyr Met Ser   1 5 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR2 of c-Met antibody <220> <221> UNSURE <222> (3) <223> X is Asn or Lys <220> <221> UNSURE <222> (4) <223> X is Ala or Val <220> <221> UNSURE <222> (7) <223> X is Asn or Thr <400> 5 Arg Asn Xaa Xaa Asn Gly Xaa Thr   1 5 <210> 6 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of c-Met antibody <220> <221> UNSURE <222> (5) <223> X is Ser or Thr <400> 6 Asp Asn Trp Leu Xaa Tyr   1 5 <210> 7 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR1 of c-Met antibody <220> <221> UNSURE <222> (4) <223> X is His, Arg, Gln or Lys <220> <221> UNSURE <12> <223> X is His or Gln <220> <221> UNSURE <222> (13) <223> X is Lys or Asn <220> <221> UNSURE <222> (9) <223> X is Ser or Trp <400> 7 Lys Ser Ser Xaa Ser Leu Leu Ala Xaa Gly Asn Xaa Xaa Asn Tyr Leu   1 5 10 15 Ala     <210> 8 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR2 of c-Met antibody <220> <221> UNSURE <222> (2) <223> X is Ala or Gly <220> <221> UNSURE <222> (4) <223> X is Thr or Lys <220> <221> UNSURE <222> (7) <223> X is Ser or Pro <400> 8 Trp Xaa Ser Xaa Arg Val Xaa   1 5 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of c-Met antibody <220> <221> UNSURE <222> (1) <223> X is Gly, Ala or Gln <220> <221> UNSURE <222> (6) <223> X is Arg, His, Ser, Ala, Gly or Lys <220> <221> UNSURE <222> (8) &Lt; 223 > X is Leu, Tyr, Phe or Met <400> 9 Xaa Gln Ser Tyr Ser Xaa Pro Xaa Thr   1 5 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR1 of AbF46 <400> 10 Lys Ser Ser Gln Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR2 of AbF46 <400> 11 Trp Ala Ser Thr Arg Val Ser   1 5 <210> 12 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of AbF46 <400> 12 Gln Gln Ser Tyr Ser Ala Pro Leu Thr   1 5 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-1 clone <400> 13 Gln Gln Ser Tyr Ser Arg Pro Tyr Thr   1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > CDR-L3 derived from L3-2 clone <400> 14 Gly Gln Ser Tyr Ser Arg Pro Leu Thr   1 5 <210> 15 <211> 9 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > CDR-L3 derived from L3-3 clone <400> 15 Ala Gln Ser Tyr Ser His Pro Phe Ser   1 5 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-5 clone <400> 16 Gln Gln Ser Tyr Ser Arg Pro Phe Thr   1 5 <210> 17 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 17 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 18 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 18 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 19 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 19 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln                  85 90 95 Ser Tyr Ser Arg Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 20 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 20 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln                  85 90 95 Ser Tyr Ser His Pro Phe Ser Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 21 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 21 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Arg Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 22 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from H11-4 clone <400> 22 Pro Glu Tyr Tyr Met Ser   1 5 <210> 23 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from YC151 clone <400> 23 Pro Asp Tyr Tyr Met Ser   1 5 <210> 24 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from YC193 clone <400> 24 Ser Asp Tyr Tyr Met Ser   1 5 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 derived from YC244 clone <400> 25 Arg Asn Asn Ala Asn Gly Asn Thr   1 5 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 derived from YC321 clone <400> 26 Arg Asn Lys Val Asn Gly Tyr Thr   1 5 <210> 27 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 derived from YC354 clone <400> 27 Asp Asn Trp Leu Ser Tyr   1 5 <210> 28 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 derived from YC374 clone <400> 28 Asp Asn Trp Leu Thr Tyr   1 5 <210> 29 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-1 clone <400> 29 Lys Ser Ser His Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 30 <211> 17 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > CDR-L1 derived from L1-3 clone <400> 30 Lys Ser Ser Arg Ser Leu Leu Ser Ser Gly Asn His Lys Asn Tyr Leu   1 5 10 15 Ala     <210> 31 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-4 clone <400> 31 Lys Ser Ser Lys Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 32 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-12 clone <400> 32 Lys Ser Ser Arg Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 33 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-22 clone <400> 33 Lys Ser Ser His Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 34 <211> 7 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > CDR-L2 derived from L2-9 clone <400> 34 Trp Ala Ser Lys Arg Val Ser   1 5 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 derived from L2-12 clone <400> 35 Trp Gly Ser Thr Arg Val Ser   1 5 <210> 36 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 derived from L2-16 clone <400> 36 Trp Gly Ser Thr Arg Val Pro   1 5 <210> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-32 clone <400> 37 Gln Gln Ser Tyr Ser Lys Pro Phe Thr   1 5 <210> 38 <211> 1416 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of heavy chain of chAbF46 <220> <221> misc_feature <222> (1) (6) <223> EcoRI restriction site <220> <221> misc_feature <222> (7). (66) <223> signal sequence <220> <221> misc_feature &Lt; 222 > (67) .. (417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418). (423) <223> NdeI restriction site <220> <221> misc_feature &Lt; 222 > (418) .. (1407) <223> CH - heavy chain constant region <220> <221> misc_feature (1408). (1410) <223> TGA - stop sodon <220> <221> misc_feature (1411). (1416) <223> XhoI restriction site <400> 38 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg tgaagctggt ggagtctgga ggaggcttgg tacagcctgg gggttctctg 120 agactctcct gtgcaacttc tgggttcacc ttcactgatt actacatgag ctgggtccgc 180 cagcctccag gaaaggcact tgagtggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cggttcacca tctccagaga taattcccaa 300 agcatcctct atcttcaaat ggacaccctg agagctgagg acagtgccac ttattactgt 360 gcaagagata actggtttgc ttactggggc caagggactc tggtcactgt ctctgcagct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1200 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380 aagagcctct ccctgtctcc gggtaaatga ctcgag 1416 <210> 39 <211> 759 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of light chain of chAbF46 <220> <221> misc_difference <222> (1) (6) <223> EcoRI restriction site <220> <221> misc_difference &Lt; 222 > (7) <223> signal sequence <220> <221> misc_difference &Lt; 222 > (91) <223> VL - light chain variable region <220> <221> misc_difference &Lt; 222 > 430 (430) <223> BsiWI restriction site <220> <221> misc_difference &Lt; 222 > (433) .. (750) <223> CL - light chain constant region <220> <221> misc_difference &Lt; 222 > (751) .. (753) <223> stop codon <220> <221> misc_difference &Lt; 222 > (754) .. (759) <223> XhoI restriction site <400> 39 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gacattttga tgacccagtc tccatcctcc 120 ctgactgtgt cagcaggaga gaaggtcact atgagctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccagc agaaaccagg acgatctcct 240 aaaatgctga taatttgggc atccactagg gtatctggag tccctgatcg cttcataggc 300 agtggatctg ggacggattt cactctgacc atcaacagtg tgcaggctga agatctggct 360 gtttattact gtcagcagtc ctacagcgct ccgctcacgt tcggtgctgg gaccaagctg 420 gagctgaaac gtacggtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 480 ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata acttctatcc cagagaggcc 540 aaagtacagt ggaaggtgga taacgccctc caatcgggta actcccagga gagtgtcaca 600 gagcaggaca gcaaggacag cacctacagc ctcagcagca ccctgacgct gagcaaagca 660 gactacgaga aacacaaagt ctacgcctgc gaagtcaccc atcagggcct gagctcgccc 720 gtcacaaaga gcttcaacag gggagagtgt tgactcgag 759 <210> 40 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H1-heavy <400> 40 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu         115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys     130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser                 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser Ser             180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn         195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His     210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu             260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 41 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H3-heavy <400> 41 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu         115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys     130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser                 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser Ser             180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn         195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His     210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu             260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 42 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H4-heavy <400> 42 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu         115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys     130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser                 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser Ser             180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn         195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His     210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu             260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 43 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H1-light <400> 43 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly   1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln          35 40 45 Pro Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 44 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H2-light <400> 44 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly   1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Leu Gln Lys Pro Gly Gln          35 40 45 Ser Pro Gln Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys  65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 45 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H3-light <400> 45 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly   1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln          35 40 45 Pro Pro Lys Leu Leu Ile Ile Trp Ala Ser Thr Arg Val 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 46 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H4-light <400> 46 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu     210 215 <210> 47 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H1-heavy <400> 47 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcact gactactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg gttgggcttt attagaaaca aagctaacgg ttacaccaca 180 gaatacagtg cgtctgtgaa aggcagattc accatctcaa gagataattc aaagaactca 240 ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg ccgtgtatta ctgtgctaga 300 gataactggt ttgcttactg gggtcaagga accctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 48 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H3-heavy <400> 48 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcact gactactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg gttgggcttt attagaaaca aagctaacgg ttacaccaca 180 gaatacagtg cgtctgtgaa aggcagattc accatctcaa gagataattc aaagaactca 240 ctgtatctgc aaatgaacag cctgcgtgct gaggacacgg ccgtgtatta ctgtgctaga 300 gataactggt ttgcttactg gggtcaagga accctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 49 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H4-heavy <400> 49 gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60 tcctgtgcag cttctggctt caccttcact gattactaca tgagctgggt gcgtcaggcc 120 ccgggtaagg gcctggaatg gttgggtttt attagaaaca aagctaatgg ttacacaaca 180 gagtacagtg catctgtgaa gggtcgtttc actataagca gagataattc caaaaacaca 240 ctgtacctgc agatgaacag cctgcgtgct gaggacactg ccgtctatta ttgtgctaga 300 gataactggt ttgcttactg gggccaaggg actctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 50 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H1-light <400> 50 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtctttta gctagcggca accaaaataa ctacttagct 120 tggcaccagc agaaaccagg acagcctcct aagatgctca ttatttgggc atctacccgg 180 gtatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaatc ctatagtgct 300 cctctcacgt tcggaggcgg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 51 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H2-light <400> 51 gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca agtccagtca gagtctttta gctagtggca accaaaataa ctacttggcc 120 tggcacctgc agaagccagg gcagtctcca cagatgctga tcatttgggc atccactagg 180 gtatctggag tcccagacag gttcagtggc agtgggtcag gcactgattt cacactgaaa 240 atcagcaggg tggaggctga ggatgttgga gtttattact gccagcagtc ctacagcgct 300 ccgctcacgt tcggacaggg taccaagctg gagctcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 52 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H3-light <400> 52 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtctttta gctagcggca accaaaataa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aagctgctca ttatttgggc atctacccgg 180 gtatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaatc ctatagtgct 300 cctctcacgt tcggaggcgg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 53 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H4-light <400> 53 gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60 atcacctgca agtccagtca gagtctttta gctagtggca accaaaataa ctacttggcc 120 tggcaccaac agaaaccagg aaaagctccg aaaatgctga ttatttgggc atccactagg 180 gtatctggag tcccttctcg cttctctgga tccgggtctg ggacggattt cactctgacc 240 atcagcagtc tgcagccgga agacttcgca acttattact gtcagcagtc ctacagcgct 300 ccgctcacgt tcggacaggg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 54 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> linker between VH and VL <400> 54 Gly Leu Gly Gly Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly   1 5 10 15 Gly Ser Ser Gly Val Gly Ser              20 <210> 55 <211> 1088 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding scFv of huAbF46 antibody <400> 55 gctagcgttt tagcagaagt tcaattggtt gaatctggtg gtggtttggt tcaaccaggt 60 ggttctttga gattgtcttg tgctgcttct ggttttactt tcaccgatta ttacatgtcc 120 tgggttagac aagctccagg taaaggtttg gaatggttgg gtttcattag aaacaaggct 180 aacggttaca ctaccgaata ttctgcttct gttaagggta gattcaccat ttctagagac 240 aactctaaga acaccttgta cttgcaaatg aactccttga gagctgaaga tactgctgtt 300 tattactgcg ctagagataa ttggtttgct tattggggtc aaggtacttt ggttactgtt 360 tcttctggcc tcgggggcct cggaggagga ggtagtggcg gaggaggctc cggtggatcc 420 agcggtgtgg gttccgatat tcaaatgacc caatctccat cttctttgtc tgcttcagtt 480 ggtgatagag ttaccattac ttgtaagtcc tcccaatctt tgttggcttc tggtaatcag 540 aacaattact tggcttggca tcaacaaaaa ccaggtaaag ctccaaagat gttgattatt 600 tgggcttcta ccagagtttc tggtgttcca tctagatttt ctggttctgg ttccggtact 660 gattttactt tgaccatttc atccttgcaa ccagaagatt tcgctactta ctactgtcaa 720 caatcttact ctgctccatt gacttttggt caaggtacaa aggtcgaaat caagagagaa 780 ttcggtaagc ctatccctaa ccctctcctc ggtctcgatt ctacgggtgg tggtggatct 840 ggtggtggtg gttctggtgg tggtggttct caggaactga caactatatg cgagcaaatc 900 ccctcaccaa ctttagaatc gacgccgtac tctttgtcaa cgactactat tttggccaac 960 gggaaggcaa tgcaaggagt ttttgaatat tacaaatcag taacgtttgt cagtaattgc 1020 ggttctcacc cctcaacaac tagcaaaggc agccccataa acacacagta tgttttttga 1080 gtttaaac 1088 <210> 56 <211> 5597 <212> DNA <213> Artificial Sequence <220> <223> expression vector including polynucleotide encoding scFv of          huAbF46 antibody <220> <221> misc_difference &Lt; 222 > (573) .. (578) <223> NheI restriction site <220> <221> misc_difference <222> (588). (938) <223> huAbF46 VH <220> <221> misc_difference <222> (939). (1007) <223> linker <220> <221> misc_difference <222> (1008). (1349) <223> huAbF46 VL <220> <221> misc_difference (1350). (1355) <223> EcoRI restriction site <220> <221> misc_difference &Lt; 222 > (1356) .. (1397) <223> V5 epitope <220> <221> misc_difference <222> (1398). (1442) <223> (G4S) 3 linker <220> <221> misc_difference <222> (1443). (1649) <223> Aga2 <220> <221> misc_difference &Lt; 222 > (1650) .. (1652) <223> TGA (stop codon) <220> <221> misc_difference &Lt; 222 > (1653) .. (1660) <223> PmeI restriction site <400> 56 acggattaga agccgccgag cgggtgacag ccctccgaag gaagactctc ctccgtgcgt 60 cctcgtcttc accggtcgcg ttcctgaaac gcagatgtgc ctcgcgccgc actgctccga 120 acaataaaga ttctacaata ctagctttta tggttatgaa gaggaaaaat tggcagtaac 180 ctggccccac aaaccttcaa atgaacgaat caaattaaca accataggat gataatgcga 240 ttagtttttt agccttattt ctggggtaat taatcagcga agcgatgatt tttgatctat 300 taacagatat ataaatgcaa aaactgcata accactttaa ctaatacttt caacattttc 360 ggtttgtatt acttcttatt caaatgtaat aaaagtatca acaaaaaatt gttaatatac 420 ctctatactt taacgtcaag gagaaaaaac cccggatcgg actactagca gctgtaatac 480 gactcactat agggaatatt aagctaattc tacttcatac attttcaatt aagatgcagt 540 tacttcgctg tttttcaata ttttctgtta ttgctagcgt tttagcagaa gttcaattgg 600 ttgaatctgg tggtggtttg gttcaaccag gtggttcttt gagattgtct tgtgctgctt 660 ctggttttac tttcaccgat tattacatgt cctgggttag acaagctcca ggtaaaggtt 720 tggaatggtt gggtttcatt agaaacaagg ctaacggtta cactaccgaa tattctgctt 780 ctgttaaggg tagattcacc atttctagag acaactctaa gaacaccttg tacttgcaaa 840 tgaactcctt gagagctgaa gatactgctg tttattactg cgctagagat aattggtttg 900 cttattgggg tcaaggtact ttggttactg tttcttctgg cctcgggggc ctcggaggag 960 gggtagtgg cggaggaggc tccggtggat ccagcggtgt gggttccgat attcaaatga 1020 cccaatctcc atcttctttg tctgcttcag ttggtgatag agttaccatt acttgtaagt 1080 cctcccaatc tttgttggct tctggtaatc agaacaatta cttggcttgg catcaacaaa 1140 aaccaggtaa agctccaaag atgttgatta tttgggcttc taccagagtt tctggtgttc 1200 catctagatt ttctggttct ggttccggta ctgattttac tttgaccatt tcatccttgc 1260 aaccagaaga tttcgctact tactactgtc aacaatctta ctctgctcca ttgacttttg 1320 gtcaaggtac aaaggtcgaa atcaagagag aattcggtaa gcctatccct aaccctctcc 1380 tcggtctcga ttctacgggt ggtggtggat ctggtggtgg tggttctggt ggtggtggtt 1440 ctcaggaact gacaactata tgcgagcaaa tcccctcacc aactttagaa tcgacgccgt 1500 actctttgtc aacgactact attttggcca acgggaaggc aatgcaagga gtttttgaat 1560 attacaaatc agtaacgttt gtcagtaatt gcggttctca cccctcaaca actagcaaag 1620 gcagccccat aaacacacag tatgtttttt gagtttaaac ccgctgatct gataacaaca 1680 gtgtagatgt aacaaaatcg actttgttcc cactgtactt ttagctcgta caaaatacaa 1740 tatacttttc atttctccgt aaacaacatg ttttcccatg taatatcctt ttctattttt 1800 cgttccgtta ccaactttac acatacttta tatagctatt cacttctata cactaaaaaa 1860 ctaagacaat tttaattttg ctgcctgcca tatttcaatt tgttataaat tcctataatt 1920 tatcctatta gtagctaaaa aaagatgaat gtgaatcgaa tcctaagaga attgggcaag 1980 tgcacaaaca atacttaaat aaatactact cagtaataac ctatttctta gcatttttga 2040 cgaaatttgc tattttgtta gagtctttta caccatttgt ctccacacct ccgcttacat 2100 caacaccaat aacgccattt aatctaagcg catcaccaac attttctggc gtcagtccac 2160 cagctaacat aaaatgtaag ctctcggggc tctcttgcct tccaacccag tcagaaatcg 2220 agttccaatc caaaagttca cctgtcccac ctgcttctga atcaaacaag ggaataaacg 2280 aatgaggttt ctgtgaagct gcactgagta gtatgttgca gtcttttgga aatacgagtc 2340 ttttaataac tggcaaaccg aggaactctt ggtattcttg ccacgactca tctccgtgca 2400 gttggacgat atcaatgccg taatcattga ccagagccaa aacatcctcc ttaggttgat 2460 tacgaaacac gccaaccaag tatttcggag tgcctgaact atttttatat gcttttacaa 2520 gacttgaaat tttccttgca ataaccgggt caattgttct ctttctattg ggcacacata 2580 taatacccag caagtcagca tcggaatcta gagcacattc tgcggcctct gtgctctgca 2640 agccgcaaac tttcaccaat ggaccagaac tacctgtgaa attaataaca gacatactcc 2700 aagctgcctt tgtgtgctta atcacgtata ctcacgtgct caatagtcac caatgccctc 2760 cctcttggcc ctctcctttt cttttttcga ccgaatttct tgaagacgaa agggcctcgt 2820 gatacgccta tttttatagg ttaatgtcat gataataatg gtttcttagg acggatcgct 2880 tgcctgtaac ttacacgcgc ctcgtatctt ttaatgatgg aataatttgg gaatttactc 2940 tgtgtttatt tatttttatg ttttgtattt ggattttaga aagtaaataa agaaggtaga 3000 agagttacgg aatgaagaaa aaaaaataaa caaaggttta aaaaatttca acaaaaagcg 3060 tactttacat atatatttat tagacaagaa aagcagatta aatagatata cattcgatta 3120 acgataagta aaatgtaaaa tcacaggatt ttcgtgtgtg gtcttctaca cagacaagat 3180 gaaacaattc ggcattaata cctgagagca ggaagagcaa gataaaaggt agtatttgtt 3240 ggcgatcccc ctagagtctt ttacatcttc ggaaaacaaa aactattttt tctttaattt 3300 ctttttttac tttctatttt taatttatat atttatatta aaaaatttaa attataatta 3360 tttttatagc acgtgatgaa aaggacccag gtggcacttt tcggggaaat gtgcgcggaa 3420 cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg agacaataac 3480 cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa catttccgtg 3540 tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac ccagaaacgc 3600 tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac atcgaactgg 3660 atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt ccaatgatga 3720 gcacttttaa agttctgcta tgtggcgcgg tattatcccg tgttgacgcc gggcaagagc 3780 aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca ccagtcacag 3840 aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc ataaccatga 3900 gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag gagctaaccg 3960 cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa ccggagctga 4020 atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg gcaacaacgt 4080 tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa ttaatagact 4140 ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg gctggctggt 4200 ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt gcagcactgg 4260 ggccagatgg taagccctcc cgtatcgtag ttatctacac gacgggcagt caggcaacta 4320 tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag cattggtaac 4380 tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat ttttaattta 4440 aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct taacgtgagt 4500 tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct tgagatcctt 4560 tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca gcggtggttt 4620 gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc agcagagcgc 4680 agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc aagaactctg 4740 tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct gccagtggcg 4800 ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag gcgcagcggt 4860 cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc tacaccgaac 4920 tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg agaaaggcgg 4980 acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag cttccagggg 5040 ggaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt gagcgtcgat 5100 ttttgtgatg ctcgtcaggg gggccgagcc tatggaaaaa cgccagcaac gcggcctttt 5160 tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg ttatcccctg 5220 attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc cgcagccgaa 5280 cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcccaata cgcaaaccgc 5340 ctctccccgc gcgttggccg attcattaat gcagctggca cgacaggttt cccgactgga 5400 aagcgggcag tgagcgcaac gcaattaatg tgagttacct cactcattag gcaccccagg 5460 ctttacactt tatgcttccg gctcctatgt tgtgtggaat tgtgagcgga taacaatttc 5520 acacaggaaa cagctatgac catgattacg ccaagctcgg aattaaccct cactaaaggg 5580 aacaaaagct ggctagt 5597 <210> 57 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> U6-HC7 hinge <400> 57 Glu Pro Lys Ser Cys Asp Cys His Cys Pro Pro Cys Pro   1 5 10 <210> 58 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-1 clone <400> 58 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtcagcagtc ctacagccgc ccgtacacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 59 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-2 clone <400> 59 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtgggcagtc ctacagccgt ccgctcacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 60 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-3 clone <400> 60 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtgcacagtc ctacagccat ccgttctctt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 61 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-5 clone <400> 61 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtcagcagtc ctacagccgc ccgtttacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 62 <211> 462 <212> PRT <213> Artificial Sequence <220> A polypeptide consisting of heavy chains of huAbF46-H4-A1, U6-HC7          hinge and constant region of human IgG1 <400> 62 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln   1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly              20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp          35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp      50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser  65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn                  85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val             100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr         115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Ser Ser Val Phe Pro     130 135 140 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn                 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln             180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser         195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser     210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Cys His 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe                 245 250 255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro             260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val         275 280 285 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr     290 295 300 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Val Ser 305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys                 325 330 335 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser             340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro         355 360 365 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val     370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp                 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp             420 425 430 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His         435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys     450 455 460 <210> 63 <211> 1410 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding polypeptide chain of heavy chain          huAbF46-H4-A1, U6-HC7 hinge and constant region of human IgG1 <400> 63 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 agctgcgatt gccactgtcc tccatgtcca gcacctgaac tcctgggggg accgtcagtc 780 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1080 gggcagcccc gagaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380 ctctccctgt ctccgggtaa atgactcgag 1410 <210> 64 <211> 461 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > polypeptide consisting of heavy chain of huAbF46-H4-A1, human          IgG2 hinge and constant region of human IgG1 <400> 64 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln   1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly              20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp          35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp      50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser  65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn                  85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val             100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr         115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Ser Ser Val Phe Pro     130 135 140 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn                 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln             180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser         195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser     210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu                 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu             260 265 270 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys         275 280 285 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys     290 295 300 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Val Ser Leu 305 310 315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys                 325 330 335 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys             340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser         355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys     370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly                 405 410 415 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln             420 425 430 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn         435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys     450 455 460 <210> 65 <211> 1407 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding polypeptide chain of heavy chain          huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG1 <400> 65 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagaggaag 720 tgctgtgtgg agtgcccccc ctgcccagca cctgaactcc tggggggacc gtcagtcttc 780 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 900 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 960 gtggtcagcg tcctcaccgt cctgcaccag gactggctta atggcaagga gtacaagtgc 1020 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1080 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380 tccctgtctc cgggtaaatg actcgag 1407 <210> 66 <211> 460 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > polypeptide consisting of heavy chain of huAbF46-H4-A1, human          IgG2 hinge and constant region of human IgG2 <400> 66 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln   1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly              20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp          35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp      50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser  65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn                  85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val             100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr         115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Ser Ser Val Phe Pro     130 135 140 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn                 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln             180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Ser Ser         195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser     210 215 220 Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe                 245 250 255 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val             260 265 270 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe         275 280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro     290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 305 310 315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val                 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr             340 345 350 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg         355 360 365 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly     370 375 380 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395 400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser                 405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln             420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His         435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys     450 455 460 <210> 67 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding polypeptide chain of heavy chain          huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG2 <400> 67 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660 acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720 tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840 gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900 gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960 gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020 gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080 ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140 gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200 agcaatgggc agccggagaa caactacaag accacgcctc ccatgctgga ctccgacggc 1260 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380 ctgtctccgg gtaaatgact cgag 1404 <210> 68 <211> 240 <212> PRT <213> Artificial Sequence <220> The polypeptide chain of light chain of huAbF46-H4-A1 (H36Y) and          human kappa constant region <400> 68 Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser   1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Leu Ser              20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser          35 40 45 Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln      50 55 60 Lys Pro Gly Lys Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg  65 70 75 80 Val Ser Gly Val Ser Ser Phe Ser Gly Ser Gly Ser Gly Thr Asp                  85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr             100 105 110 Tyr Cys Gln Gln Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr         115 120 125 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe     130 135 140 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val                 165 170 175 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln             180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser         195 200 205 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His     210 215 220 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240 <210> 69 <211> 758 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding a polypeptide consisting of light chains of          huAbF46-H4-A1 (H36Y) and human kappa constant region <400> 69 aattcactag tgattaattc gccgccacca tggattcaca ggcccaggtc ctcatgttgc 60 tgctgctatc ggtatctggt acctgtggag atatccagat gacccagtcc ccgagctccc 120 tgtccgcctc tgtgggcgat agggtcacca tcacctgcaa gtccagtcag agtcttttag 180 ctagtggcaa ccaaaataac tacttggcct ggtaccaaca gaaaccagga aaagctccga 240 aaatgctgat tatttgggca tccactaggg tatctggagt cccttctcgc ttctctggat 300 ccgggtctgg gacggatttc actctgacca tcagcagtct gcagccggaa gacttcgcaa 360 cttattactg tcagcagtcc tacagccgcc cgtacacgtt cggacagggt accaaggtgg 420 agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct gatgagcagt 480 tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc agagaggcca 540 aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag agtgtcacag 600 agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg agcaaagcag 660 actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg agctcgcccg 720 tcacaaagag cttcaacagg ggagagtgtt gactcgag 758 <210> 70 <211> 240 <212> PRT <213> Artificial Sequence <220> <223> A polypeptide consisting of light chains of huAbF46-H4-A1 and human          kappa constant region <400> 70 Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser   1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Leu Ser              20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser          35 40 45 Leu Leu Ala Ser Gly Asn Gln Asn Asn His Leu Ala Trp Tyr Gln Gln      50 55 60 Lys Pro Gly Lys Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg  65 70 75 80 Val Ser Gly Val Ser Ser Phe Ser Gly Ser Gly Ser Gly Thr Asp                  85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr             100 105 110 Tyr Cys Gln Gln Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr         115 120 125 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe     130 135 140 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val                 165 170 175 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln             180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser         195 200 205 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His     210 215 220 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240 <210> 71 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> The epitope in the SEMA domain of c-Met <400> 71 Phe Ser Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro Asp Cys Val Val   1 5 10 15 Ser Ala Leu             <210> 72 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> The epitope in the SEMA domain of c-Met <400> 72 Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro   1 5 10 <210> 73 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> The epitope in the SEMA domain of c-Met <400> 73 Glu Glu Pro Ser Gln   1 5 <210> 74 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of anti-c-Met antibody (AbF46 or          huAbF46-H1) <400> 74 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 75 <211> 114 <212> PRT <213> Artificial Sequence <220> The light chain variable region of anti-c-Met antibody (AbF46 or          huAbF46-H1) <400> 75 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly   1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln          35 40 45 Pro Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 76 <211> 1416 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of heavy chain of nti-c-Met antibody (AbF46          or huAbF46-H1) <220> <221> misc_feature <222> (1) (6) <223> EcoRI restriction site <220> <221> misc_feature <222> (7). (66) <223> signal sequence <220> <221> misc_feature &Lt; 222 > (67) .. (417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418). (423) <223> NdeI restriction site <220> <221> misc_feature &Lt; 222 > (418) .. (1407) <223> CH - heavy chain constant region <220> <221> misc_feature (1408). (1410) <223> TGA - stop sodon <220> <221> misc_feature (1411). (1416) <223> XhoI restriction site <400> 76 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg tgaagctggt ggagtctgga ggaggcttgg tacagcctgg gggttctctg 120 agactctcct gtgcaacttc tgggttcacc ttcactgatt actacatgag ctgggtccgc 180 cagcctccag gaaaggcact tgagtggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cggttcacca tctccagaga taattcccaa 300 agcatcctct atcttcaaat ggacaccctg agagctgagg acagtgccac ttattactgt 360 gcaagagata actggtttgc ttactggggc caagggactc tggtcactgt ctctgcagct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1200 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380 aagagcctct ccctgtctcc gggtaaatga ctcgag 1416 <210> 77 <211> 759 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of light chain of anti-c-Met antibody (AbF46          or huAbF46-H1) <220> <221> misc_difference <222> (1) (6) <223> EcoRI restriction site <220> <221> misc_difference &Lt; 222 > (7) <223> signal sequence <220> <221> misc_difference &Lt; 222 > (91) <223> VL - light chain variable region <220> <221> misc_difference &Lt; 222 > 430 (430) <223> BsiWI restriction site <220> <221> misc_difference &Lt; 222 > (433) .. (750) <223> CL - light chain constant region <220> <221> misc_difference &Lt; 222 > (751) .. (753) <223> stop codon <220> <221> misc_difference &Lt; 222 > (754) .. (759) <223> XhoI restriction site <400> 77 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gacattttga tgacccagtc tccatcctcc 120 ctgactgtgt cagcaggaga gaaggtcact atgagctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccagc agaaaccagg acgatctcct 240 aaaatgctga taatttgggc atccactagg gtatctggag tccctgatcg cttcataggc 300 agtggatctg ggacggattt cactctgacc atcaacagtg tgcaggctga agatctggct 360 gtttattact gtcagcagtc ctacagcgct ccgctcacgt tcggtgctgg gaccaagctg 420 gagctgaaac gtacggtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 480 ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata acttctatcc cagagaggcc 540 aaagtacagt ggaaggtgga taacgccctc caatcgggta actcccagga gagtgtcaca 600 gagcaggaca gcaaggacag cacctacagc ctcagcagca ccctgacgct gagcaaagca 660 gactacgaga aacacaaagt ctacgcctgc gaagtcaccc atcagggcct gagctcgccc 720 gtcacaaaga gcttcaacag gggagagtgt tgactcgag 759 <210> 78 <211> 4170 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding c-Met protein <400> 78 atgaaggccc ccgctgtgct tgcacctggc atcctcgtgc tcctgtttac cttggtgcag 60 aggagcaatg gggagtgtaa agaggcacta gcaaagtccg agatgaatgt gaatatgaag 120 tatcagcttc ccaacttcac cgcggaaaca cccatccaga atgtcattct acatgagcat 180 cacattttcc ttggtgccac taactacatt tatgttttaa atgaggaaga ccttcagaag 240 gttgctgagt acaagactgg gcctgtgctg gaacacccag attgtttccc atgtcaggac 300 tgcagcagca aagccaattt atcaggaggt gtttggaaag ataacatcaa catggctcta 360 gttgtcgaca cctactatga tgatcaactc attagctgtg gcagcgtcaa cagagggacc 420 tgccagcgac atgtctttcc ccacaatcat actgctgaca tacagtcgga ggttcactgc 480 atattctccc cacagataga agagcccagc cagtgtcctg actgtgtggt gagcgccctg 540 ggagccaaag tcctttcatc tgtaaaggac cggttcatca acttctttgt aggcaatacc 600 ataaattctt cttatttccc agatcatcca ttgcattcga tatcagtgag aaggctaaag 660 gaaacgaaag atggttttat gtttttgacg gaccagtcct acattgatgt tttacctgag 720 ttcagagatt cttaccccat taagtatgtc catgcctttg aaagcaacaa ttttatttac 780 ttcttgacgg tccaaaggga aactctagat gctcagactt ttcacacaag aataatcagg 840 ttctgttcca taaactctgg attgcattcc tacatggaaa tgcctctgga gtgtattctc 900 acagaaaaga gaaaaaagag atccacaaag aaggaagtgt ttaatatact tcaggctgcg 960 tatgtcagca agcctggggc ccagcttgct agacaaatag gagccagcct gaatgatgac 1020 attcttttcg gggtgttcgc acaaagcaag ccagattctg ccgaaccaat ggatcgatct 1080 gccatgtgtg cattccctat caaatatgtc aacgacttct tcaacaagat cgtcaacaaa 1140 aacaatgtga gatgtctcca gcatttttac ggacccaatc atgagcactg ctttaatagg 1200 acacttctga gaaattcatc aggctgtgaa gcgcgccgtg atgaatatcg aacagagttt 1260 accacagctt tgcagcgcgt tgacttattc atgggtcaat tcagcgaagt cctcttaaca 1320 tctatatcca ccttcattaa aggagacctc accatagcta atcttgggac atcagagggt 1380 cgcttcatgc aggttgtggt ttctcgatca ggaccatcaa cccctcatgt gaattttctc 1440 ctggactccc atccagtgtc tccagaagtg attgtggagc atacattaaa ccaaaatggc 1500 tacacactgg ttatcactgg gaagaagatc acgaagatcc cattgaatgg cttgggctgc 1560 agacatttcc agtcctgcag tcaatgcctc tctgccccac cctttgttca gtgtggctgg 1620 tgccacgaca aatgtgtgcg atcggaggaa tgcctgagcg ggacatggac tcaacagatc 1680 tgtctgcctg caatctacaa ggttttccca aatagtgcac cccttgaagg agggacaagg 1740 ctgaccatat gtggctggga ctttggattt cggaggaata ataaatttga tttaaagaaa 1800 actagagttc tccttggaaa tgagagctgc accttgactt taagtgagag cacgatgaat 1860 acattgaaat gcacagttgg tcctgccatg aataagcatt tcaatatgtc cataattatt 1920 tcaaatggcc acgggacaac acaatacagt acattctcct atgtggatcc tgtaataaca 1980 agtatttcgc cgaaatacgg tcctatggct ggtggcactt tacttacttt aactggaaat 2040 tacctaaaca gtgggaattc tagacacatt tcaattggtg gaaaaacatg tactttaaaa 2100 agtgtgtcaa acagtattct tgaatgttat accccagccc aaaccatttc aactgagttt 2160 gctgttaaat tgaaaattga cttagccaac cgagagacaa gcatcttcag ttaccgtgaa 2220 gatcccattg tctatgaaat tcatccaacc aaatctttta ttagtggtgg gagcacaata 2280 acaggtgttg ggaaaaacct gaattcagtt agtgtcccga gaatggtcat aaatgtgcat 2340 gaagcaggaa ggaactttac agtggcatgt caacatcgct ctaattcaga gataatctgt 2400 tgtaccactc cttccctgca acagctgaat ctgcaactcc ccctgaaaac caaagccttt 2460 ttcatgttag atgggatcct ttccaaatac tttgatctca tttatgtaca taatcctgtg 2520 tttaagcctt ttgaaaagcc agtgatgatc tcaatgggca atgaaaatgt actggaaatt 2580 aagggaaatg atattgaccc tgaagcagtt aaaggtgaag tgttaaaagt tggaaataag 2640 agctgtgaga atatacactt acattctgaa gccgttttat gcacggtccc caatgacctg 2700 ctgaaattga acagcgagct aaatatagag tggaagcaag caatttcttc aaccgtcctt 2760 ggaaaagtaa tagttcaacc agatcagaat ttcacaggat tgattgctgg tgttgtctca 2820 atatcaacag cactgttatt actacttggg tttttcctgt ggctgaaaaa gagaaagcaa 2880 attaaagatc tgggcagtga attagttcgc tacgatgcaa gagtacacac tcctcatttg 2940 gataggcttg taagtgcccg aagtgtaagc ccaactacag aaatggtttc aaatgaatct 3000 gtagactacc gagctacttt tccagaagat cagtttccta attcatctca gaacggttca 3060 tgccgacaag tgcagtatcc tctgacagac atgtccccca tcctaactag tggggactct 3120 gatatatcca gtccattact gcaaaatact gtccacattg acctcagtgc tctaaatcca 3180 gagctggtcc aggcagtgca gcatgtagtg attgggccca gtagcctgat tgtgcatttc 3240 ggattggt gatggcaaga aaattcactg tgctgtgaaa tccttgaaca gaatcactga cataggagaa 3360 gtttcccaat ttctgaccga gggaatcatc atgaaagatt ttagtcatcc caatgtcctc 3420 tcgctcctgg gaatctgcct gcgaagtgaa gggtctccgc tggtggtcct accatacatg 3480 aaacatggag atcttcgaaa tttcattcga aatgagactc ataatccaac tgtaaaagat 3540 cttattggct ttggtcttca agtagccaaa ggcatgaaat atcttgcaag caaaaagttt 3600 gtccacagag acttggctgc aagaaactgt atgctggatg aaaaattcac agtcaaggtt 3660 gctgattttg gtcttgccag agacatgtat gataaagaat actatagtgt acacaacaaa 3720 acaggtgcaa agctgccagt gaagtggatg gctttggaaa gtctgcaaac tcaaaagttt 3780 accaccaagt cagatgtgtg gtcctttggc gtgctcctct gggagctgat gacaagagga 3840 gccccacctt atcctgacgt aaacaccttt gatataactg tttacttgtt gcaagggaga 3900 agactcctac aacccgaata ctgcccagac cccttatatg aagtaatgct aaaatgctgg 3960 cccctaaag ccgaaatgcg cccatccttt tctgaactgg tgtcccggat atcagcgatc 4020 ttctctactt tcattgggga gcactatgtc catgtgaacg ctacttatgt gaacgtaaaa 4080 tgtgtcgctc cgtatccttc tctgttgtca tcagaagata acgctgatga tgaggtggac 4140 acacgaccag cctccttctg ggagacatca 4170 <210> 79 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> SEMA domain of c-Met <400> 79 Leu His Glu His Ile Phe Leu Gly Ala Thr Asn Tyr Ile Tyr Val   1 5 10 15 Leu Asn Glu Glu Asp Leu Gln Lys Val Ala Glu Tyr Lys Thr Gly Pro              20 25 30 Val Leu Glu His Pro Asp Cys Phe Pro Cys Gln Asp Cys Ser Ser Lys          35 40 45 Ala Asn Leu Ser Gly Gly Val Trp Lys Asp Asn Ile Asn Met Ala Leu      50 55 60 Val Val Asp Thr Tyr Tyr Asp Asp Gln Leu Ile Ser Cys Gly Ser Val  65 70 75 80 Asn Arg Gly Thr Cys Gln Arg His Val Phe Pro His Asn His Thr Ala                  85 90 95 Asp Ile Gln Ser Glu Val His Cys Ile Phe Ser Pro Gln Ile Glu Glu             100 105 110 Pro Ser Gln Cys Pro Asp Cys Val Val Ser Ala Leu Gly Ala Lys Val         115 120 125 Leu Ser Ser Val Lys Asp Arg Phe Ile Asn Phe Phe Val Gly Asn Thr     130 135 140 Ile Asn Ser Ser Tyr Phe Pro Asp His Pro Leu His Ser Ser Ser 145 150 155 160 Arg Arg Leu Lys Glu Thr Lys Asp Gly Phe Met Phe Leu Thr Asp Gln                 165 170 175 Ser Tyr Ile Asp Val Leu Pro Glu Phe Arg Asp Ser Tyr Pro Ile Lys             180 185 190 Tyr Val His Ala Phe Glu Ser Asn Asn Phe Ile Tyr Phe Leu Thr Val         195 200 205 Gln Arg Glu Thr Leu Asp Ala Gln Thr Phe His Thr Arg Ile Ile Arg     210 215 220 Phe Cys Ser Ile Asn Ser Gly Leu His Ser Tyr Met Glu Met Pro Leu 225 230 235 240 Glu Cys Ile Leu Thr Glu Lys Arg Lys Lys Arg Ser Thr Lys Lys Glu                 245 250 255 Val Phe Asn Ile Leu Gln Ala Ala Tyr Val Ser Lys Pro Gly Ala Gln             260 265 270 Leu Ala Arg Gln Ile Gly Ala Ser Leu Asn Asp Asp Ile Leu Phe Gly         275 280 285 Val Phe Ala Gln Ser Lys Pro Asp Ser Ala Glu Pro Met Asp Arg Ser     290 295 300 Ala Met Cys Ala Phe Pro Ile Lys Tyr Val Asn Asp Phe Phe Asn Lys 305 310 315 320 Ile Val Asn Lys Asn Asn Val Arg Cys Leu Gln His Phe Tyr Gly Pro                 325 330 335 Asn His Glu His Cys Phe Asn Arg Thr Leu Leu Arg Asn Ser Ser Gly             340 345 350 Cys Glu Ala Arg Arg Asp Glu Tyr Arg Thr Glu Phe Thr Thr Ala Leu         355 360 365 Gln Arg Val Asp Leu Phe Met Gly Gln Phe Ser Glu Val Leu Leu Thr     370 375 380 Ser Ile Ser Thr Phe Ile Lys Gly Asp Leu Thr Ile Ala Asn Leu Gly 385 390 395 400 Thr Ser Glu Gly Arg Phe Met Gln Val Val Val Ser Ser Ser Gly Pro                 405 410 415 Ser Thr Pro His Val Asn Phe Leu Leu Asp Ser His Pro Val Ser Pro             420 425 430 Glu Val Ile Val Glu His Thr Leu Asn Gln Asn Gly         435 440 <210> 80 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> PSI-IPT domain of c-Met <400> 80 Tyr Thr Leu Val Ile Thr Gly Lys Lys Ile Thr Lys Ile Pro Leu Asn   1 5 10 15 Gly Leu Gly Cys Arg His Phe Gln Ser Cys Ser Gln Cys Leu Ser Ala              20 25 30 Pro Pro Phe Val Gln Cys Gly Trp Cys His Asp Lys Cys Val Arg Ser          35 40 45 Glu Glu Cys Leu Ser Gly Thr Trp Thr Gln Gln Ile Cys Leu Pro Ala      50 55 60 Ile Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu Gly Gly Thr Arg  65 70 75 80 Leu Thr Ile Cys Gly Trp Asp Phe Gly Phe Arg Arg Asn Asn Lys Phe                  85 90 95 Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu Ser Cys Thr Leu             100 105 110 Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys Thr Val Gly Pro         115 120 125 Ala Met Asn Lys His Phe Asn Met Ser Ile Ile Ile Ser Asn Gly His     130 135 140 Gly Thr Thr Gln Tyr Ser Thr Phe Ser Tyr Val Asp Pro Val Ile Thr 145 150 155 160 Ser Ile Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly Thr Leu Leu Thr                 165 170 175 Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Ser His Ile Ser Ile             180 185 190 Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn Ser Ile Leu Glu         195 200 205 Cys Tyr Thr Pro Ala Gln Thr Ile Ser Thr Glu Phe Ala Val Lys Leu     210 215 220 Lys Ile Asp Leu Ala Asn Arg Glu Thr Ser Ile Phe Ser Tyr Arg Glu 225 230 235 240 Asp Pro Ile Val Tyr Glu Ile His Pro Thr Lys Ser Phe Ile Ser Thr                 245 250 255 Trp Trp Lys Glu Pro Leu Asn Ile Val Ser Phe Leu Phe Cys Phe Ala             260 265 270 Ser Gly Gly Ser Thr Ile Thr Gly Val Gly Lys Asn Leu Asn Ser Val         275 280 285 Ser Val Pro Arg Met Val Ile Asn Val His Glu Ala Gly Arg Asn Phe     290 295 300 Thr Val Ala Cys Gln His Arg Ser Asn Ser Glu Ile Ile Cys Cys Thr 305 310 315 320 Thr Pro Ser Leu Gln Gln Leu Asn Leu Gln Leu Pro Leu Lys Thr Lys                 325 330 335 Ala Phe Phe Met Leu Asp Gly Ile Leu Ser Lys Tyr Phe Asp Leu Ile             340 345 350 Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys Pro Val Met Ile         355 360 365 Ser Met Gly Asn Glu Asn Val Leu Glu Ile Lys Gly Asn Asp Ile Asp     370 375 380 Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly Asn Lys Ser Cys 385 390 395 400 Glu Asn Ile His Leu His Ser Glu Ala Val Leu Cys Thr Val Pro Asn                 405 410 415 Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn Ile Glu Trp Lys Gln Ala             420 425 430 Ile Ser Ser Thr Val Leu Gly Lys Val Ile Val Gln Pro Asp Gln Asn         435 440 445 Phe Thr Gly     450 <210> 81 <211> 313 <212> PRT <213> Artificial Sequence <220> <223> TyrKc domain of c-Met <400> 81 Val His Phe Asn Glu Val Ile Gly Arg Gly His Phe Gly Cys Val Tyr   1 5 10 15 His Gly Thr Leu Leu Asp Asn Asp Gly Lys Lys Ile His Cys Ala Val              20 25 30 Lys Ser Leu Asn Arg Ile Thr Asp Ile Gly Glu Val Ser Gln Phe Leu          35 40 45 Thr Glu Gly Ile Ile Met Lys Asp Phe Ser His Pro Asn Val Leu Ser      50 55 60 Leu Leu Gly Ile Cys Leu Arg Ser Glu Gly Ser Pro Leu Val Val Leu  65 70 75 80 Pro Tyr Met Lys His Gly Asp Leu Arg Asn Phe Ile Arg Asn Glu Thr                  85 90 95 His Asn Pro Thr Val Lys Asp Leu Ile Gly Phe Gly Leu Gln Val Ala             100 105 110 Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe Val His Arg Asp Leu         115 120 125 Ala Ala Arg Asn Cys Met Leu Asp Glu Lys Phe Thr Val Lys Val Ala     130 135 140 Asp Phe Gly Leu Ala Arg Asp Met Tyr Asp Lys Glu Tyr Tyr Ser Val 145 150 155 160 His Asn Lys Thr Gly Ala Lys Leu Pro Val Lys Trp Met Ala Leu Glu                 165 170 175 Ser Leu Gln Thr Gln Lys Phe Thr Thr Lys Ser Asp Val Trp Ser Phe             180 185 190 Gly Val Leu Leu Trp Glu Leu Met Thr Arg Gly Ala Pro Pro Tyr Pro         195 200 205 Asp Val Asn Thr Phe Asp Ile Thr Val Tyr Leu Leu Gln Gly Arg Arg     210 215 220 Leu Leu Gln Pro Glu Tyr Cys Pro Asp Pro Leu Tyr Glu Val Met Leu 225 230 235 240 Lys Cys Trp His Pro Lys Ala Glu Met Arg Pro Ser Phe Ser Glu Leu                 245 250 255 Val Ser Arg Ile Ser Ala Ile Phe Ser Thr Phe Ile Gly Glu His Tyr             260 265 270 Val His Val Asn Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr         275 280 285 Pro Ser Leu Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp Thr     290 295 300 Arg Pro Ala Ser Phe Trp Glu Thr Ser 305 310 <210> 82 <211> 1332 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding SEMA domain of c-Met <400> 82 ctacatgagc atcacatttt ccttggtgcc actaactaca tttatgtttt aaatgaggaa 60 gaccttcaga aggttgctga gtacaagact gggcctgtgc tggaacaccc agattgtttc 120 ccatgtcagg actgcagcag caaagccaat ttatcaggag gtgtttggaa agataacatc 180 aacatggctc tagttgtcga cacctactat gatgatcaac tcattagctg tggcagcgtc 240 aacagaggga cctgccagcg acatgtcttt ccccacaatc atactgctga catacagtcg 300 gaggttcact gcatattctc cccacagata gaagagccca gccagtgtcc tgactgtgtg 360 gtgagcgccc tgggagccaa agtcctttca tctgtaaagg accggttcat caacttcttt 420 gtaggcaata ccataaattc ttcttatttc ccagatcatc cattgcattc gatatcagtg 480 agaaggctaa aggaaacgaa agatggtttt atgtttttga cggaccagtc ctacattgat 540 gttttacctg agttcagaga ttcttacccc attaagtatg tccatgcctt tgaaagcaac 600 aattttattt acttcttgac ggtccaaagg gaaactctag atgctcagac ttttcacaca 660 agaataatca ggttctgttc cataaactct ggattgcatt cctacatgga aatgcctctg 720 gagtgtattc tcacagaaaa gagaaaaaag agatccacaa agaaggaagt gtttaatata 780 cttcaggctg cgtatgtcag caagcctggg gcccagcttg ctagacaaat aggagccagc 840 ctgaatgatg acattctttt cggggtgttc gcacaaagca agccagattc tgccgaacca 900 atggatcgat ctgccatgtg tgcattccct atcaaatatg tcaacgactt cttcaacaag 960 atcgtcaaca aaaacaatgt gagatgtctc cagcattttt acggacccaa tcatgagcac 1020 tgctttaata ggacacttct gagaaattca tcaggctgtg aagcgcgccg tgatgaatat 1080 cgaacagagt ttaccacagc tttgcagcgc gttgacttat tcatgggtca attcagcgaa 1140 gtcctcttaa catctatatc caccttcatt aaaggagacc tcaccatagc taatcttggg 1200 acatcagagg gtcgcttcat gcaggttgtg gtttctcgat caggaccatc aacccctcat 1260 gtgaattttc tcctggactc ccatccagtg tctccagaag tgattgtgga gcatacatta 1320 aaccaaaatg gc 1332 <210> 83 <211> 1299 <212> DNA <213> Artificial Sequence <220> <223> Polynucleotide encoding PSI-IPT domain of c-Met <400> 83 tacacactgg ttatcactgg gaagaagatc acgaagatcc cattgaatgg cttgggctgc 60 agacatttcc agtcctgcag tcaatgcctc tctgccccac cctttgttca gtgtggctgg 120 tgccacgaca aatgtgtgcg atcggaggaa tgcctgagcg ggacatggac tcaacagatc 180 tgtctgcctg caatctacaa ggttttccca aatagtgcac cccttgaagg agggacaagg 240 ctgaccatat gtggctggga ctttggattt cggaggaata ataaatttga tttaaagaaa 300 actagagttc tccttggaaa tgagagctgc accttgactt taagtgagag cacgatgaat 360 acattgaaat gcacagttgg tcctgccatg aataagcatt tcaatatgtc cataattatt 420 tcaaatggcc acgggacaac acaatacagt acattctcct atgtggatcc tgtaataaca 480 agtatttcgc cgaaatacgg tcctatggct ggtggcactt tacttacttt aactggaaat 540 tacctaaaca gtgggaattc tagacacatt tcaattggtg gaaaaacatg tactttaaaa 600 agtgtgtcaa acagtattct tgaatgttat accccagccc aaaccatttc aactgagttt 660 gctgttaaat tgaaaattga cttagccaac cgagagacaa gcatcttcag ttaccgtgaa 720 gatcccattg tctatgaaat tcatccaacc aaatctttta ttagtggtgg gagcacaata 780 acaggtgttg ggaaaaacct gaattcagtt agtgtcccga gaatggtcat aaatgtgcat 840 gaagcaggaa ggaactttac agtggcatgt caacatcgct ctaattcaga gataatctgt 900 tgtaccactc cttccctgca acagctgaat ctgcaactcc ccctgaaaac caaagccttt 960 ttcatgttag atgggatcct ttccaaatac tttgatctca tttatgtaca taatcctgtg 1020 tttaagcctt ttgaaaagcc agtgatgatc tcaatgggca atgaaaatgt actggaaatt 1080 aagggaaatg atattgaccc tgaagcagtt aaaggtgaag tgttaaaagt tggaaataag 1140 agctgtgaga atatacactt acattctgaa gccgttttat gcacggtccc caatgacctg 1200 ctgaaattga acagcgagct aaatatagag tggaagcaag caatttcttc aaccgtcctt 1260 ggaaaagtaa tagttcaacc agatcagaat ttcakhga 1299 <210> 84 <211> 939 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding TyrKc domain of c-Met <400> 84 gtgcatttca atgaagtcat aggaagaggg cattttggtt gtgtatatca tgggactttg 60 ttggacaatg atggcaagaa aattcactgt gctgtgaaat ccttgaacag aatcactgac 120 ataggagaag tttcccaatt tctgaccgag ggaatcatca tgaaagattt tagtcatccc 180 aatgtcctct cgctcctggg aatctgcctg cgaagtgaag ggtctccgct ggtggtccta 240 ccatacatga aacatggaga tcttcgaaat ttcattcgaa atgagactca taatccaact 300 gtaaaagatc ttattggctt tggtcttcaa gtagccaaag gcatgaaata tcttgcaagc 360 aaaaagtttg tccacagaga cttggctgca agaaactgta tgctggatga aaaattcaca 420 gtcaaggttg ctgattttgg tcttgccaga gacatgtatg ataaagaata ctatagtgta 480 cacaacaaaa caggtgcaaa gctgccagtg aagtggatgg ctttggaaag tctgcaaact 540 ggagctgatg 600 acaagaggag ccccacctta tcctgacgta aacacctttg atataactgt ttacttgttg 660 caagggagaa gactcctaca acccgaatac tgcccagacc ccttatatga agtaatgcta 720 aaatgctggc accctaaagc cgaaatgcgc ccatcctttt ctgaactggt gtcccggata 780 tcagcgatct tctctacttt cattggggag cactatgtcc atgtgaacgc tacttatgtg 840 aacgtaaaat gtgtcgctcc gtatccttct ctgttgtcat cagaagataa cgctgatgat 900 gaggtggaca cacgaccagc ctccttctgg gagacatca 939 <210> 85 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of anti-c-Met antibody <400> 85 Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val   1 5 10 <210> 86 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of anti-c-Met antibody <400> 86 Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu   1 5 10 <210> 87 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of monoclonal antibody AbF46 <400> 87 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile  65 70 75 80 Leu Tyr Leu Gln Met Asp Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ala         115 <210> 88 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti-c-Met antibody <400> 88 Asp Ile Leu Met Thr Gln Ser Ser Ser Leu Thr Val Ser Ala Gly   1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Arg          35 40 45 Ser Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Asn Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu             100 105 110 Lys Arg         <210> 89 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of anti-c-Met antibody <400> 89 Gln Gln Ser Tyr Ser Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu   1 5 10 15 Glu     <210> 90 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH1 <400> 90 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Ser Ser Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Thr Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 91 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH2 <400> 91 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Ser Ser Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 92 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH3 <400> 92 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Ser Ser Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 93 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH4 <400> 93 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 94 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH5 <400> 94 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser         115 <210> 95 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized          antibody (huAbF46-H4) <400> 95 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 96 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk1 <400> 96 Asp Ile Leu Met Thr Gln Ser Ser Ser Leu Thr Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Asp Arg Phe Ile 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile             100 105 110 Lys     <210> 97 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk2 <400> 97 Asp Ile Leu Met Thr Gln Ser Ser Ser Ser Ser Ser Ser Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Asp Arg Phe Ile 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile             100 105 110 Lys     <210> 98 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk3 <400> 98 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Asp Arg Phe Ile 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile             100 105 110 Lys     <210> 99 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk4 <400> 99 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val 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 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile             100 105 110 Lys     <210> 100 <211> 13 <212> PRT <213> Artificial Sequence <220> The modified hinge region (U7-HC6) <400> 100 Glu Pro Ser Cys Asp Lys His Cys Cys Pro Pro Cys Pro   1 5 10 <210> 101 <211> 13 <212> PRT <213> Artificial Sequence <220> The modified hinge region (U6-HC7) <400> 101 Glu Pro Lys Ser Cys Asp Cys His Cys Pro Pro Cys Pro   1 5 10 <210> 102 <211> 12 <212> PRT <213> Artificial Sequence <220> Modified hinge region (U3-HC9) <400> 102 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro   1 5 10 <210> 103 <211> 14 <212> PRT <213> Artificial Sequence <220> The modified hinge region (U6-HC8) <400> 103 Glu Pro Arg Asp Cys Gly Cys Lys Pro Cys Pro Pro Cys Pro   1 5 10 <210> 104 <211> 13 <212> PRT <213> Artificial Sequence <220> The modified hinge region (U8-HC5) <400> 104 Glu Lys Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro   1 5 10 <210> 105 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> human hinge region <400> 105 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro   1 5 10 15 <210> 106 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of antibody L3-11Y <400> 106 Lys Ser Ser Gln Ser Leu Leu Ala Trp Gly Asn Gln Asn Asn Tyr Leu   1 5 10 15 Ala     <210> 107 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of light chain variable region of antibody          L3-11Y <400> 107 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Trp              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg         <210> 108 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of light chain of antibody L3-11Y <400> 108 Asp Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ala Ser Val Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Trp              20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys          35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val      50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr  65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln                  85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 109 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> variable heavy chain domain VH of anti-ANG-2 antibody <400> 109 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 Gly Tyr              20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met          35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe      50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr  65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr             100 105 110 Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser         115 120 125 <210> 110 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> variable light chain domain VL of anti-ANG-2 antibody <400> 110 Gln Pro Gly Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln   1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val              20 25 30 His Trp Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr          35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser      50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly  65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His                  85 90 95 Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu             100 105 <210> 111 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> Signal peptide <400> 111 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly   1 5 10 15 Val His Ser             <210> 112 <211> 57 <212> DNA <213> Artificial Sequence <220> <223> Signal peptide coding gene <400> 112 atgggatggt catgtatcat cctttttcta gtagcaactg caactggagt acattca 57 <210> 113 <211> 254 <212> PRT <213> Artificial Sequence <220> Anti-cMet scFv, where the sequence "GGGGSGGGGSGGSSGVGS" from          123rd to 140th prositions is a linker <400> 113 Glu Val Gln Leu Val 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 Thr Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu          35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala      50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr  65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr                  85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser Gly Leu Gly Gly Leu Gly Gly Gly Gly Gly Ser Gly         115 120 125 Gly Gly Gly Ser Gly Gly Ser Ser Gly Val Gly Ser Asp Ile Gln Met     130 135 140 Thr Gln Ser Ser Ser Ser Ser Ser Val Ser Ser Val Gly Asp Arg Val Thr 145 150 155 160 Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ser Ser Gly Asn Gln Asn                 165 170 175 Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys Ala Pro Lys Met             180 185 190 Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Ser Val Val Ser Ser Phe         195 200 205 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu     210 215 220 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Ser Arg 225 230 235 240 Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg                 245 250 <210> 114 <211> 762 <212> DNA <213> Artificial Sequence <220> <223> Anti-cMet scFv coding gene <400> 114 gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60 tcctgtgcag cttctggctt caccttcact gattactaca tgagctgggt gcgtcaggcc 120 ccgggtaagg gcctggaatg gttgggtttt attagaaaca aagctaatgg ttacacaaca 180 gagtacagtg catctgtgaa gggtcgtttc actataagca gagataattc caaaaacaca 240 ctgtacctgc agatgaacag cctgcgtgct gaggacactg ccgtctatta ttgtgctaga 300 gataactggt ttgcttactg gggccaaggg actctggtca ccgtctcctc gggcctgggc 360 ggcctgggcg gaggaggctc tggaggcggc ggaagcggcg gcagcagcgg cgtgggcagc 420 gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 480 atcacctgca agtccagtca gagtctttta gctagtggca accaaaataa ctacttggcc 540 tggcaccaac agaaaccagg aaaagctccg aaaatgctga ttatttgggc atccactagg 600 gtatctggag tcccttctcg cttctctggg tccgggtctg ggacggattt cactctgacc 660 atcagcagtc tgcagccgga agacttcgca acttattact gtcagcagtc ctacagccgc 720 ccgtacacgt tcggacaggg taccaaggtg gagatcaaac gt 762 <210> 115 <211> 232 <212> PRT <213> Artificial Sequence <220> <223> Hinge-Fc without Knob-into-hole <400> 115 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala   1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro              20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val          35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val      50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln  65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln                  85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala             100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro         115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr     130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr                 165 170 175 Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr             180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe         195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys     210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210> 116 <211> 696 <212> DNA <213> Artificial Sequence <220> <223> DNA encioding Hinge-Fc without Knob-into-hole <400> 116 gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60 gggggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 240 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420 gaagagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 600 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660 tacacgcaga agagcctctc cctgtctccg ggtaaa 696 <210> 117 <211> 76 <212> PRT <213> Artificial Sequence <220> <223> ubiquitin <400> 117 Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu   1 5 10 15 Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp              20 25 30 Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys          35 40 45 Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu      50 55 60 Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly  65 70 75 <210> 118 <211> 228 <212> DNA <213> Artificial Sequence <220> <223> Ubiquitin coding gene <400> 118 atgcagatct tcgtgaaaac cctgaccggc aagaccatca ccctggaagt ggaacccagc 60 gacaccatcg agaacgtgaa ggccaagatc caggacaaag agggcatccc ccccgaccag 120 cagagactga tcttcgccgg caagcagctg gaagatggca gaaccctgag cgactacaac 180 atccagaaag agtccaccct gcacctggtg ctgcggctga gaggcgga 228 <210> 119 <211> 2 <212> PRT <213> Artificial Sequence <220> <223> GS linker <400> 119 Gly Ser 119 <210> 120 <211> 6 <212> DNA <213> Artificial Sequence <220> <223> GS linker coding gene <400> 120 ggatcc 6 <210> 121 <211> 251 <212> PRT <213> Artificial Sequence <220> Anti-Ang2 scFv, where the sequence "GGGGSGGGGSGGGGS" from 129th          to 143th prositions is a linker <400> 121 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 Gly Tyr              20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met          35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe      50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr  65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr             100 105 110 Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser         115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gln     130 135 140 Pro Gly Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln Thr 145 150 155 160 Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His                 165 170 175 Trp Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr Asp             180 185 190 Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn         195 200 205 Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp     210 215 220 Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His Tyr 225 230 235 240 Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu                 245 250 <210> 122 <211> 753 <212> DNA <213> Artificial Sequence <220> <223> Anti-Ang2 scFv coding gene <400> 122 caggtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcgccag cgtgaaggtg 60 agctgcaagg ccagcggcta caccttcacc ggctactaca tgcactgggt gcgccaggcc 120 cccggccagg gcctggagtg gatgggctgg atcaacccca acagcggcgg caccaactac 180 gcccagaagt tccagggccg cgtgaccatg acccgcgaca ccagcatcag caccgcctac 240 atggagctga gccgcctgcg cagcgacgac accgccgtgt actactgcgc ccgcagcccc 300 aacccctact actacgacag cagcggctac tactaccccg gcgccttcga catctggggc 360 cagggcacca tggtgaccgt gagcggcggc ggcggcagcg gcggcggcgg cagcggcggc 420 ggcggcagcc agcccggcct gacccagccc cccagcgtga gcgtggcccc cggccagacc 480 gcccgcatca cctgcggcgg caacaacatc ggcagcaaga gcgtgcactg gtaccagcag 540 aagcccggcc aggcccccgt gctggtggtg tacgacgaca gcgaccgccc cagcggcatc 600 cccgagcgct tcagcggcag caacagcggc aacaccgcca ccctgaccat cagccgcgtg 660 gaggccggcg acgaggccga ctactactgc caggtgtggg acagcagcag cgaccactac 720 gtgttcggca ccggcaccaa ggtgaccgtg ctg 753 <210> 123 <211> 232 <212> PRT <213> Artificial Sequence <220> <223> amino acid of Hinge-Fc with Knob, where 151th amino acid "Y" is          knob <400> 123 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala   1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro              20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val          35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val      50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln  65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln                  85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala             100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro         115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr     130 135 140 Lys Asn Gln Val Ser Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr                 165 170 175 Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr             180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe         195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys     210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210> 124 <211> 696 <212> DNA <213> Artificial Sequence <220> <223> gene encoding Hinge-Fc with Knob <400> 124 gagcccaaga gctgcgacaa gacccacacc tgccccccct gccccgcccc cgagctgctg 60 ggcggcccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagccgc 120 acccccgagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 180 aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagccccg cgaggagcag 240 tacaacagca cctaccgcgt ggtgagcgtg ctgaccgtgc tgcaccagga ctggctgaac 300 ggcaaggagt acaagtgcaa ggtgagcaac aaggccctgc ccgcccccat cgagaagacc 360 atcagcaagg ccaagggcca gccccgcgag ccccaggtgt acaccctgcc ccccagccgc 420 gaggagatga ccaagaacca ggtgagcctg tactgcctgg tgaagggctt ctaccccagc 480 gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 540 cccgtgctgg acagcgacgg cagcttcttc ctgtacagca agctgaccgt ggacaagagc 600 cgctggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 660 tacacccaga agagcctgag cctgagcccc ggcaag 696 <210> 125 <211> 232 <212> PRT <213> Artificial Sequence <220> &Lt; 223 > amino acid of Hinge-Fc with Hole, wherein the 192th amino acid,          "T", is hole <400> 125 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala   1 5 10 15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro              20 25 30 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val          35 40 45 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val      50 55 60 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln  65 70 75 80 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln                  85 90 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala             100 105 110 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro         115 120 125 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr     130 135 140 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 145 150 155 160 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr                 165 170 175 Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Thr             180 185 190 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe         195 200 205 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys     210 215 220 Ser Leu Ser Leu Ser Pro Gly Lys 225 230 <210> 126 <211> 696 <212> DNA <213> Artificial Sequence <220> <223> gene encoding Hinge-Fc with Hole <400> 126 gagcccaaga gctgcgacaa gacccacacc tgccccccct gccccgcccc cgagctgctg 60 ggcggcccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagccgc 120 acccccgagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 180 aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagccccg cgaggagcag 240 tacaacagca cctaccgcgt ggtgagcgtg ctgaccgtgc tgcaccagga ctggctgaac 300 ggcaaggagt acaagtgcaa ggtgagcaac aaggccctgc ccgcccccat cgagaagacc 360 atcagcaagg ccaagggcca gccccgcgag ccccaggtgt acaccctgcc ccccagccgc 420 gaggagatga ccaagaacca ggtgagcctg acctgcctgg tgaagggctt ctaccccagc 480 gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 540 cccgtgctgg acagcgacgg cagcttcttc ctgaccagca agctgaccgt ggacaagagc 600 cgctggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 660 tacacccaga agagcctgag cctgagcccc ggcaag 696 <210> 127 <211> 1066 <212> PRT <213> Artificial Sequence <220> Polypeptide (bispecific antibody) without knob-into-hole <400> 127 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly   1 5 10 15 Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln              20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr Phe          35 40 45 Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu      50 55 60 Glu Trp Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu  65 70 75 80 Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser                  85 90 95 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr             100 105 110 Ala Val Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln         115 120 125 Gly Thr Leu Val Thr Val Ser Ser Gly Leu Gly Gly Leu Gly Gly Gly     130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser Ser Gly Val Gly Ser Ser 145 150 155 160 Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ser Ser Val Gly Asp                 165 170 175 Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser Gly             180 185 190 Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys Ala         195 200 205 Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val Pro     210 215 220 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 225 230 235 240 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser                 245 250 255 Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             260 265 270 Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro         275 280 285 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys     290 295 300 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 305 310 315 320 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr                 325 330 335 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu             340 345 350 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His         355 360 365 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys     370 375 380 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 385 390 395 400 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met                 405 410 415 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro             420 425 430 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn         435 440 445 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu     450 455 460 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 465 470 475 480 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln                 485 490 495 Lys Ser Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr             500 505 510 Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile         515 520 525 Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp     530 535 540 Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr 545 550 555 560 Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu                 565 570 575 Arg Leu Arg Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala             580 585 590 Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser         595 600 605 Gly Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro     610 615 620 Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly 625 630 635 640 Thr Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp                 645 650 655 Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp             660 665 670 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr         675 680 685 Asp Ser Ser Gly Tyr Tyr Tyr Pro Gly Ala Phe Asp Ile Trp Gly Gln     690 695 700 Gly Thr Met Val Thr Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly 705 710 715 720 Ser Gly Gly Gly Gly Ser Gln Pro Gly Leu Thr Gln Pro Pro Ser Val                 725 730 735 Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn             740 745 750 Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala         755 760 765 Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro     770 775 780 Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile 785 790 795 800 Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp                 805 810 815 Asp Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys Val Thr             820 825 830 Val Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys         835 840 845 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro     850 855 860 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 865 870 875 880 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp                 885 890 895 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu             900 905 910 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu         915 920 925 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn     930 935 940 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 945 950 955 960 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu                 965 970 975 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr             980 985 990 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn         995 1000 1005 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe    1010 1015 1020 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 1025 1030 1035 1040 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr                1045 1050 1055 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys            1060 1065 <210> 128 <211> 3201 <212> DNA <213> Artificial Sequence <220> <223> gene encodign the polypeptide of SEQ ID NO 127 <400> 128 atgggatggt catgtatcat cctttttcta gtagcaactg caactggagt acattcagag 60 gttcagctgg tggagtctgg cggtggcctg gtgcagccag ggggctcact ccgtttgtcc 120 tgtgcagctt ctggcttcac cttcactgat tactacatga gctgggtgcg tcaggccccg 180 ggtaagggcc tggaatggtt gggttttatt agaaacaaag ctaatggtta cacaacagag 240 tacagtgcat ctgtgaaggg tcgtttcact ataagcagag ataattccaa aaacacactg 300 tacctgcaga tgaacagcct gcgtgctgag gacactgccg tctattattg tgctagagat 360 aactggtttg cttactgggg ccaagggact ctggtcaccg tctcctcggg cctgggcggc 420 ctgggcggcg gcggcagcgg cggcggcggc agcggcggca gcagcggcgt gggcagcgat 480 atccagatga cccagtcccc gagctccctg tccgcctctg tgggcgatag ggtcaccatc 540 acctgcaagt ccagtcagag tcttttagct agtggcaacc aaaataacta cttggcctgg 600 caccaacaga aaccaggaaa agctccgaaa atgctgatta tttgggcatc cactagggta 660 tctggagtcc cttctcgctt ctctggctcc gggtctggga cggatttcac tctgaccatc 720 agcagtctgc agccggaaga cttcgcaact tattactgtc agcagtccta cagccgcccg 780 tacacgttcg gacagggtac caaggtggag atcaaacgtg agcccaaatc ttgtgacaaa 840 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggcccgtc agtcttcctc 900 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 960 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1020 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 1080 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1140 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1200 ccccgagaac cacaggtgta caccctgccc ccatcccggg aagagatgac caagaaccag 1260 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1320 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1380 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1440 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1500 ctgtctccgg gtaaaatgca gatcttcgtg aaaaccctga ccggcaagac catcaccctg 1560 gaagtggaac ccagcgacac catcgagaac gtgaaggcca agatccagga caaagagggc 1620 atcccccccg accagcagag actgatcttc gccggcaagc agctggaaga tggcagaacc 1680 ctgagcgact acaacatcca gaaagagtcc accctgcacc tggtgctgcg gctgagaggc 1740 ggaggatccc aggtgcagct ggtgcagagc ggcgccgagg tgaagaagcc cggcgccagc 1800 gtgaaggtga gctgcaaggc cagcggctac accttcaccg gctactacat gcactgggtg 1860 cgccaggccc ccggccaggg cctggagtgg atgggctgga tcaaccccaa cagcggcggc 1920 accaactacg cccagaagtt ccagggccgc gtgaccatga cccgcgacac cagcatcagc 1980 accgcctaca tggagctgag ccgcctgcgc agcgacgaca ccgccgtgta ctactgcgcc 2040 cgcagcccca acccctacta ctacgacagc agcggctact actaccccgg cgccttcgac 2100 atctggggcc agggcaccat ggtgaccgtg agcggcggcg gcggcagcgg cggcggcggc 2160 agcggcggcg gcggcagcca gcccggcctg acccagcccc ccagcgtgag cgtggccccc 2220 ggccagaccg cccgcatcac ctgcggcggc aacaacatcg gcagcaagag cgtgcactgg 2280 taccagcaga agcccggcca ggcccccgtg ctggtggtgt acgacgacag cgaccgcccc 2340 agcggcatcc ccgagcgctt cagcggcagc aacagcggca acaccgccac cctgaccatc 2400 agccgcgtgg aggccggcga cgaggccgac tactactgcc aggtgtggga cagcagcagc 2460 gaccactacg tgttcggcac cggcaccaag gtgaccgtgc tggagcccaa atcttgtgac 2520 aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 2580 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 2640 gtggtggtcg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 2700 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 2760 gtggtcagcg tcctcaccgt cctgcaccag gactggctta atggcaagga gtacaagtgc 2820 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 2880 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaagagat gaccaagaac 2940 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 3000 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 3060 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 3120 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 3180 tccctgtctc cgggtaaatg a 3201 <210> 129 <211> 1066 <212> PRT <213> Artificial Sequence <220> <223> polypepetide (bispecific antibody) with Knob-into-hole <400> 129 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly   1 5 10 15 Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln              20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Phe Thr Phe          35 40 45 Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu      50 55 60 Glu Trp Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu  65 70 75 80 Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser                  85 90 95 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr             100 105 110 Ala Val Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln         115 120 125 Gly Thr Leu Val Thr Val Ser Ser Gly Leu Gly Gly Leu Gly Gly Gly     130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser Ser Gly Val Gly Ser Ser 145 150 155 160 Ile Gln Met Thr Gln Ser Ser Ser Leu Ser Ser Ser Val Gly Asp                 165 170 175 Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser Gly             180 185 190 Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys Ala         195 200 205 Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val Pro     210 215 220 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 225 230 235 240 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser                 245 250 255 Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             260 265 270 Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro         275 280 285 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys     290 295 300 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 305 310 315 320 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr                 325 330 335 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu             340 345 350 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His         355 360 365 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys     370 375 380 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 385 390 395 400 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met                 405 410 415 Thr Lys Asn Gln Val Ser Leu Tyr Cys Leu Val Lys Gly Phe Tyr Pro             420 425 430 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn         435 440 445 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu     450 455 460 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 465 470 475 480 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln                 485 490 495 Lys Ser Leu Ser Leu Ser Pro Gly Lys Met Gln Ile Phe Val Lys Thr             500 505 510 Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile         515 520 525 Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp     530 535 540 Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr 545 550 555 560 Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu                 565 570 575 Arg Leu Arg Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala             580 585 590 Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser         595 600 605 Gly Tyr Thr Phe Thr Gly Tyr Tyr Met His Trp Val Arg Gln Ala Pro     610 615 620 Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly 625 630 635 640 Thr Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp                 645 650 655 Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp             660 665 670 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Pro Asn Pro Tyr Tyr Tyr         675 680 685 Asp Ser Ser Gly Tyr Tyr Tyr Pro Gly Ala Phe Asp Ile Trp Gly Gln     690 695 700 Gly Thr Met Val Thr Val Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly 705 710 715 720 Ser Gly Gly Gly Gly Ser Gln Pro Gly Leu Thr Gln Pro Pro Ser Val                 725 730 735 Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn             740 745 750 Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala         755 760 765 Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro     770 775 780 Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile 785 790 795 800 Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp                 805 810 815 Asp Ser Ser Asp His Tyr Val Phe Gly Thr Gly Thr Lys Val Thr             820 825 830 Val Leu Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys         835 840 845 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro     850 855 860 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 865 870 875 880 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp                 885 890 895 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu             900 905 910 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu         915 920 925 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn     930 935 940 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 945 950 955 960 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu                 965 970 975 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr             980 985 990 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn         995 1000 1005 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe    1010 1015 1020 Leu Thr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 1025 1030 1035 1040 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr                1045 1050 1055 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys            1060 1065 <210> 130 <211> 3201 <212> DNA <213> Artificial Sequence <220> <223> gene coding the polypeptide of SEQ ID NO: 129 <400> 130 atgggatggt catgtatcat cctttttcta gtagcaactg caactggagt acattcagag 60 gttcagctgg tggagtctgg cggtggcctg gtgcagccag ggggctcact ccgtttgtcc 120 tgtgcagctt ctggcttcac cttcactgat tactacatga gctgggtgcg tcaggccccg 180 ggtaagggcc tggaatggtt gggttttatt agaaacaaag ctaatggtta cacaacagag 240 tacagtgcat ctgtgaaggg tcgtttcact ataagcagag ataattccaa aaacacactg 300 tacctgcaga tgaacagcct gcgtgctgag gacactgccg tctattattg tgctagagat 360 aactggtttg cttactgggg ccaagggact ctggtcaccg tctcctcggg cctgggcggc 420 ctgggcggag gaggctctgg aggcggcgga agcggcggca gcagcggcgt gggcagcgat 480 atccagatga cccagtcccc gagctccctg tccgcctctg tgggcgatag ggtcaccatc 540 acctgcaagt ccagtcagag tcttttagct agtggcaacc aaaataacta cttggcctgg 600 caccaacaga aaccaggaaa agctccgaaa atgctgatta tttgggcatc cactagggta 660 tctggagtcc cttctcgctt ctctgggtcc gggtctggga cggatttcac tctgaccatc 720 agcagtctgc agccggaaga cttcgcaact tattactgtc agcagtccta cagccgcccg 780 tacacgttcg gacagggtac caaggtggag atcaaacgtg agcccaagag ctgcgacaag 840 acccacacct gccccccctg ccccgccccc gagctgctgg gcggccccag cgtgttcctg 900 ttccccccca agcccaagga caccctgatg atcagccgca cccccgaggt gacctgcgtg 960 gtggtggacg tgagccacga ggaccccgag gtgaagttca actggtacgt ggacggcgtg 1020 gaggtgcaca acgccaagac caagccccgc gaggagcagt acaacagcac ctaccgcgtg 1080 gtgagcgtgc tgaccgtgct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1140 gtgagcaaca aggccctgcc cgcccccatc gagaagacca tcagcaaggc caagggccag 1200 ccccgcgagc cccaggtgta caccctgccc cccagccgcg aggagatgac caagaaccag 1260 gtgagcctgt actgcctggt gaagggcttc taccccagcg acatcgccgt ggagtgggag 1320 agcaacggcc agcccgagaa caactacaag accacccccc ccgtgctgga cagcgacggc 1380 agcttcttcc tgtacagcaa gctgaccgtg gacaagagcc gctggcagca gggcaacgtg 1440 ttcagctgca gcgtgatgca cgaggccctg cacaaccact acacccagaa gagcctgagc 1500 ctgagccccg gcaagatgca gatcttcgtg aagaccctga ccggcaagac catcaccctg 1560 gaggtggagc ccagcgacac catcgagaac gtgaaggcca agatccagga caaggagggc 1620 atcccccccg accagcagcg cctgatcttc gccggcaagc agctggagga cggccgcacc 1680 ctgagcgact acaacatcca gaaggagagc accctgcacc tggtgctgcg cctgcgcggc 1740 ggcggatccc aggtgcagct ggtgcagagc ggcgccgagg tgaagaagcc cggcgccagc 1800 gtgaaggtga gctgcaaggc cagcggctac accttcaccg gctactacat gcactgggtg 1860 cgccaggccc ccggccaggg cctggagtgg atgggctgga tcaaccccaa cagcggcggc 1920 accaactacg cccagaagtt ccagggccgc gtgaccatga cccgcgacac cagcatcagc 1980 accgcctaca tggagctgag ccgcctgcgc agcgacgaca ccgccgtgta ctactgcgcc 2040 cgcagcccca acccctacta ctacgacagc agcggctact actaccccgg cgccttcgac 2100 atctggggcc agggcaccat ggtgaccgtg agcggaggcg gcggaagcgg cggaggaggc 2160 tctggcggcg gcggaagcca gcccggcctg acccagcccc ccagcgtgag cgtggccccc 2220 ggccagaccg cccgcatcac ctgcggcggc aacaacatcg gcagcaagag cgtgcactgg 2280 taccagcaga agcccggcca ggcccccgtg ctggtggtgt acgacgacag cgaccgcccc 2340 agcggcatcc ccgagcgctt cagcggcagc aacagcggca acaccgccac cctgaccatc 2400 agccgcgtgg aggccggcga cgaggccgac tactactgcc aggtgtggga cagcagcagc 2460 gaccactacg tgttcggcac cggcaccaag gtgaccgtgc tggagcccaa gagctgcgac 2520 aagacccaca cctgcccccc ctgccccgcc cccgagctgc tgggcggccc cagcgtgttc 2580 ctgttccccc ccaagcccaa ggacaccctg atgatcagcc gcacccccga ggtgacctgc 2640 gtggtggtgg acgtgagcca cgaggacccc gaggtgaagt tcaactggta cgtggacggc 2700 gtggaggtgc acaacgccaa gaccaagccc cgcgaggagc agtacaacag cacctaccgc 2760 gtggtgagcg tgctgaccgt gctgcaccag gactggctga acggcaagga gtacaagtgc 2820 aaggtgagca acaaggccct gcccgccccc atcgagaaga ccatcagcaa ggccaagggc 2880 cagccccgcg agccccaggt gtacaccctg ccccccagcc gcgaggagat gaccaagaac 2940 caggtgagcc tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg 3000 gagagcaacg gccagcccga gaacaactac aagaccaccc cccccgtgct ggacagcgac 3060 ggcagcttct tcctgaccag caagctgacc gtggacaaga gccgctggca gcagggcaac 3120 gtgttcagct gcagcgtgat gcacgaggcc ctgcacaacc actacaccca gaagagcctg 3180 agcctgagcc ccggcaagtg a 3201 <210> 131 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) Xaa is Asp (D), Ser (S), or Asn (N) <220> <221> UNSURE <222> (3) Xaa is Ala (A), Asp (D), or Tyr (Y) <400> 131 Xaa Tyr Xaa Met Ser   1 5 <210> 132 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) Xaa is Ala (A), GIy (G), Leu (L), or Ser (S) <220> <221> UNSURE <222> (3) Xaa is Tyr (Y) or Ser (S) <220> <221> UNSURE <222> (4) Xaa is Pro (P), His (H), or Ser (S) <220> <221> UNSURE <222> (5) Xaa is Asp (D), Gly (G), or Ser (S) <220> <221> UNSURE <222> (6) Xaa is Ser (S), Gly (G), or Asp (D) <220> <221> UNSURE <222> (7) Xaa is Gly (G) or Ser (S) <220> <221> UNSURE <222> (8) Xaa is Asn (N) or Ser (S) <220> <221> UNSURE <222> (9) Xaa is Lys (K), Ile (I), or Thr (T) <400> 132 Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 133 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) Xaa is Ser (S) or Thr (T) <220> <221> UNSURE <222> (9) Xaa is Asn (N) or Ser (S) <220> <221> UNSURE <222> (11) Xaa is Ala (A), Tyr (Y), or Asp (D) <220> <221> UNSURE <222> (13) (N), Ser (S), Thr (T), or Tyr (Y) <400> 133 Xaa Gly Ser Ser Ser Asn Ile Gly Xaa Asn Xaa Val Xaa   1 5 10 <210> 134 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) &Lt; 223 > Xaa is Ala (A) or Ser (S) <220> <221> UNSURE <222> (2) Xaa is Asp (D) or Asn (N) <220> <221> UNSURE <222> (3) Xaa is Ser (S) or Asn (N) <220> <221> UNSURE <222> (4) Xaa is Asn (N), Lys (K), His (H), or Gln (Q) <400> 134 Xaa Xaa Xaa Xaa Arg Pro Ser   1 5 <210> 135 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) <223> Xaa is Gly (G) or Ala (A) <220> <221> UNSURE <222> (2) Xaa is Ser (S), Ala (A) or Thr (T) <220> <221> UNSURE <222> (5) Xaa is Tyr (Y) or Asp (D) <220> <221> UNSURE <222> (8) Xaa is Ser (S) or Asn (N) <220> <221> UNSURE <222> (9) <223> Xaa is Gly (G) or Ala (A) <400> 135 Xaa Xaa Trp Asp Xaa Ser Leu Xaa Xaa   1 5 <210> 136 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <220> <221> UNSURE <222> (1) Xaa is Arg (R) or Tyr (Y) <220> <221> UNSURE <222> (2) <223> Xaa is Ala (A) or Thr (T) <220> <221> UNSURE <222> (4) Xaa is Asn (N), Arg (R), or Ser (S) <220> <221> UNSURE <222> (5) Xaa is Leu (L) or Arg (R) <220> <221> UNSURE <222> (6) Xaa is Asp (D), His (H), or Tyr (Y) <220> <221> UNSURE <222> (7) Xaa is Ser (S) or Pro (P) <400> 136 Xaa Xaa Ser Xaa Xaa Xaa Xaa   1 5 <210> 137 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <220> <221> UNSURE <222> (3) Xaa is Ser (S), Gly (G), Asp (D) or Tyr (Y) <220> <221> UNSURE <222> (4) Xaa is Asn (N), Tyr (Y), or Ser (S) <220> <221> UNSURE <222> (5) Xaa is Glu (E), Thr (T), or Lys (K) <220> <221> UNSURE <222> (6) Xaa is Asp (D), Ser (S), or Leu (L) <220> <221> UNSURE <222> (8) Xaa is Leu (L), Trp (W), or Tyr (Y) <400> 137 Gln Gln Xaa Xaa Xaa Xaa Pro Xaa Thr   1 5 <210> 138 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <220> <221> UNSURE <222> (3) <223> Ser (S) or Asn (N) <220> <221> UNSURE <222> (5) <223> Ser (S) or Arg (R) <220> <221> UNSURE <222> (7) <223> Ser (S) or Asn (N) <220> <221> UNSURE <222> (9) <223> Ser (S) or Asp (D) <400> 138 Tyr Ile Xaa Tyr Xaa Gly Xaa Thr Xaa Tyr Asn Pro Ser Leu Lys Ser   1 5 10 15 <210> 139 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <220> <221> UNSURE <222> (5) Ser (S), Thr (T), or Arg (R) <220> <221> UNSURE <222> (8) Pro (P), Leu (L), or Trp (W) <400> 139 Gln Gln Asp Tyr Xaa Ser Pro Xaa Thr   1 5 <210> 140 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 140 Asp Tyr Ala Met Ser   1 5 <210> 141 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 141 Asp Tyr Tyr Met Ser   1 5 <210> 142 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 142 Asn Tyr Ala Met Ser   1 5 <210> 143 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 143 Asp Tyr Ala Met Ser   1 5 <210> 144 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 144 Asp Tyr Asp Met Ser   1 5 <210> 145 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 145 Asp Tyr Ala Met Ser   1 5 <210> 146 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 146 Ser Tyr Asp Met Ser   1 5 <210> 147 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 147 Asp Tyr Asp Met Ser   1 5 <210> 148 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 148 Ala Ile Tyr Pro Asp Ser Gly Asn Lys Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 149 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 149 Gly Ile Tyr Pro Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 150 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 150 Ser Ser Gly Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Mar   1 5 10 15 Gly     <210> 151 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 151 Ser Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 152 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 152 Ser Ile Ser His Gly Asp Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 153 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 153 Ser Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 154 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 154 Leu Ile Ser Pro Asp Ser Ser Ser Ile Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 155 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 155 Gly Ile Ser Ser Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys   1 5 10 15 Gly     <210> 156 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 156 Ala Arg His Ser Ser Asp Pro Lys Val Lys Ser Gly Tyr Tyr Asp Asp   1 5 10 15 Gly Met Asp Val              20 <210> 157 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 157 Ala Arg Asp Pro Ser Thr Leu Thr Tyr Ala Gly Phe Asp Tyr   1 5 10 <210> 158 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 158 Ala Lys Ser Gly Ile Gln Pro Ser Pro Pro Ser Met Ser Ser Ala Tyr   1 5 10 15 Ala Met Asp Val              20 <210> 159 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 159 Ala Arg His Thr Ser His His Thr Ser Ile Asp Gly Tyr Tyr Tyr Tyr   1 5 10 15 Gly Met Asp Gly              20 <210> 160 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 160 Ala Lys Ser Ser Gly Ile Gln Glu Ser Pro Thr Tyr Tyr Tyr Tyr   1 5 10 15 Gly Met Asp Val              20 <210> 161 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 161 Ala Lys His Pro Val Arg Leu Asn Leu His Pro Met Tyr Tyr Tyr Tyr   1 5 10 15 Gly Met Asp Val              20 <210> 162 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 162 Ala Lys Asp Leu Ile Ser Phe Trp Arg Gly Gly Phe Asp Tyr   1 5 10 <210> 163 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 163 Ala Arg Pro Thr Ile Asp Lys Tyr Thr Leu Arg Gly Tyr Tyr Ser Tyr   1 5 10 15 Gly Met Asp Val              20 <210> 164 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 164 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Asn   1 5 10 <210> 165 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 165 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Thr   1 5 10 <210> 166 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 166 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Tyr   1 5 10 <210> 167 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 167 Thr Gly Ser Ser Asn Ile Gly Asn Asn Asp Val Ser   1 5 10 <210> 168 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 168 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ala Val Asn   1 5 10 <210> 169 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 169 Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Ser   1 5 10 <210> 170 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 170 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn   1 5 10 <210> 171 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 171 Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Ser   1 5 10 <210> 172 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 172 Ala Asp Ser Asn Arg Pro Ser   1 5 <210> 173 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 173 Ala Asp Ser His Arg Pro Ser   1 5 <210> 174 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 174 Ala Asn Ser His Arg Pro Ser   1 5 <210> 175 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 175 Ser Asp Ser Lys Arg Pro Ser   1 5 <210> 176 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 176 Ala Asp Ser Asn Arg Pro Ser   1 5 <210> 177 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 177 Ser Asp Ser Gln Arg Pro Ser   1 5 <210> 178 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 178 Ser Asp Ser His Arg Pro Ser   1 5 <210> 179 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 179 Ser Asp Asn Lys Arg Pro Ser   1 5 <210> 180 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 180 Gly Ser Trp Asp Tyr Ser Leu Ser Gly   1 5 <210> 181 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 181 Ala Thr Trp Asp Tyr Ser Leu Ser Gly   1 5 <210> 182 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 182 Gly Thr Trp Asp Tyr Ser Leu Ser Gly   1 5 <210> 183 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 183 Gly Ser Trp Asp Tyr Ser Leu Ser Gly   1 5 <210> 184 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 184 Gly Ser Trp Asp Tyr Ser Leu Ser Gly   1 5 <210> 185 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 185 Ala Thr Trp Asp Tyr Ser Leu Ser Ala   1 5 <210> 186 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 186 Gly Ala Trp Asp Asp Ser Leu Ser Gly   1 5 <210> 187 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 187 Gly Thr Trp Asp Asp Ser Leu Asn Gly   1 5 <210> 188 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 188 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Thr 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 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Tyr Pro Asp Ser Gly 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 His Ser Ser Asp Pro Lys Val Lys Ser Gly Tyr Tyr Asp Asp             100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Ala Val Ser Ser         115 120 125 <210> 189 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 189 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 Asp Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Gly Ile Tyr Pro 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 Arg Asp Pro Ser Thr Leu Thr Tyr Ala Gly Phe Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 190 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 190 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 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 Ser Gly Gly Gly Asn Ile 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 Ser Gly Ile Gln Pro Ser Pro Pro Ser Met Ser Ser Ala Tyr             100 105 110 Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 191 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 191 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 Asp Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ser Ile Tyr Pro Asp Asp Gly Asn 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 Arg His Thr Ser His His Thr Ser Ile Asp Gly Tyr Tyr Tyr Tyr             100 105 110 Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 192 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 192 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 Asp Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ser Ile Ser His Gly Asp 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 Ser Ser Gly Ile Gln Glu Ser Pro Thr Tyr Tyr Tyr Tyr             100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 193 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 193 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Thr 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 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ser Ile Tyr Pro Asp Asp Gly Asn 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 His Pro Val Arg Leu Asn Leu His Pro Met Tyr Tyr Tyr Tyr             100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 194 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 194 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 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Leu Ile Ser Pro Asp Ser Ser Ser Ile 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 Leu Ile Ser Phe Trp Arg Gly Gly Phe Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 195 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 195 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 Asp Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Gly Ile Ser Ser Asp Asp Gly Asn 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 Arg Pro Thr Ile Asp Lys Tyr Thr Leu Arg Gly Tyr Tyr Ser Tyr             100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 125 <210> 196 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 196 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 Asn Asn              20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asp Ser Asn 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 Gly Ser Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 197 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 197 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 Asn Asn              20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asp Ser His 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 Thr Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 198 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 198 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 Asn Asn              20 25 30 Asp Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asn Ser His 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 Gly Thr Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 199 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 199 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 Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn              20 25 30 Asp Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ser Asp Ser Lys 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 Gly Ser Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 200 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 200 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 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asp Ser Asn 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 Gly Ser Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 201 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 201 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 Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn              20 25 30 Ala Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ser Asp Ser 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 Thr Trp Asp Tyr Ser Leu                  85 90 95 Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 202 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 202 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 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asp Ser Asn 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 Gly Ser Trp Asp Tyr Ser Leu                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 203 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 203 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 Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn              20 25 30 Tyr Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ser Asp Asn Lys 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 Gly Thr Trp Asp Asp Ser Leu                  85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 204 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 204 Ser Tyr Trp Leu Glu   1 5 <210> 205 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 205 Asp Pro Tyr Ile His   1 5 <210> 206 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 206 Asp Tyr Tyr Met Lys   1 5 <210> 207 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 207 Asn Tyr Gly Met Asn   1 5 <210> 208 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 208 Glu Ile Leu Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe Arg   1 5 10 15 Gly     <210> 209 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 209 Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln   1 5 10 15 Gly     <210> 210 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 210 Glu Ile Asn Pro Lys Asn Gly Asp Thr Phe Tyr Asn Gln Ile Phe Lys   1 5 10 15 Gly     <210> 211 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 211 Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys   1 5 10 15 Gly     <210> 212 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 212 Gly Asn His Asn Ser Tyr Tyr Tyr Ala Met Asp Tyr   1 5 10 <210> 213 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 213 Arg Trp Asp Gly Gly Gly Phe Asp Tyr   1 5 <210> 214 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 214 Glu Asn Asp Tyr Asp Val Gly Phe Phe Asp Tyr   1 5 10 <210> 215 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 215 Asp His Asp Gly Tyr Leu Met Asp Tyr   1 5 <210> 216 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 216 Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met His   1 5 10 15 <210> 217 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 217 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn   1 5 10 <210> 218 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 218 Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala   1 5 10 <210> 219 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 219 Ser Thr Ser Gln Gly Ile Ser Asn Tyr Leu Asn   1 5 10 <210> 220 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 220 Arg Ala Ser Asn Leu Asp Ser   1 5 <210> 221 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 221 Tyr Thr Ser Arg Leu His Ser   1 5 <210> 222 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 222 Tyr Ala Ser Asn Arg Tyr Pro   1 5 <210> 223 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 223 Tyr Thr Ser Ser Leu His Ser   1 5 <210> 224 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 224 Gln Gln Ser Asn Glu Asp Pro Leu Thr   1 5 <210> 225 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 225 Gln Gln Gly Asn Thr Leu Pro Trp Thr   1 5 <210> 226 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 226 Gln Gln Asp Tyr Thr Ser Pro Trp Thr   1 5 <210> 227 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 227 Gln Gln Tyr Ser Lys Leu Pro Tyr Thr   1 5 <210> 228 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 228 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Met Lys Pro Gly Ala   1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Thr Asp Tyr Thr Phe Ser Ser Tyr              20 25 30 Trp Leu Glu Trp Leu Ile Gln Arg Pro Gly His Gly Leu Glu Trp Ile          35 40 45 Gly Ile Leu Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe      50 55 60 Arg Gly Lys Ala Thr Phe Thr Glu Asp Thr Ser Ser Asn Thr Ala Tyr  65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly Asn His Asn Ser Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser         115 120 <210> 229 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 229 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala   1 5 10 15 Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Pro              20 25 30 Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile          35 40 45 Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe      50 55 60 Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr  65 70 75 80 Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Val Arg Arg Trp Asp Gly Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Ser Val Thr Val Ser Ser         115 <210> 230 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 230 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp   1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr              20 25 30 Tyr Met Lys Trp Val Arg Gln Ser His Gly Lys Ser Leu Gln Trp Val          35 40 45 Gly Glu Ile Asn Pro Lys Asn Gly Asp Thr Phe Tyr Asn Gln Ile Phe      50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr  65 70 75 80 Met Gln Leu Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys                  85 90 95 Thr Arg Glu Asn Asp Tyr Asp Val Gly Phe Phe Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Ser Val Thr Val Ser Ser         115 120 <210> 231 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 231 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu   1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr              20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met          35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe      50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr  65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys                  85 90 95 Ala Arg Asp His Asp Gly Tyr Leu Met Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Ser Val Thr Val Ser Ser         115 <210> 232 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 232 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly   1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr              20 25 30 Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro          35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Asp Ser Gly Ile Pro Ala      50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn  65 70 75 80 Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn                  85 90 95 Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys             100 105 110 <210> 233 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 233 Asp Ile Gln Met Thr Gln Thr Ser Ser Leu Ser Ala Ser Leu Gly   1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr              20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile          35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Ser Ser Arg Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Thr Asn Leu Glu Gln  65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp                  85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 234 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 234 Thr Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Ile Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp              20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Pro Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Trp                  85 90 95 Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys             100 105 <210> 235 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 235 Asp Ile Gln Met Thr Gln Thr Ser Ser Leu Ser Ala Ser Leu Gly   1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Thr Ser Gln Gly Ile Ser Asn Tyr              20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile          35 40 45 Phe Tyr Thr Ser Ser Leu His Ser Gly Val Ser Ser Arg Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro  65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Leu Pro Tyr                  85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 236 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 of anti-Ang2 antibody <400> 236 Asp Tyr Ala Trp Asn   1 5 <210> 237 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 237 Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys Ser   1 5 10 15 <210> 238 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 238 Tyr Ile Asn Tyr Arg Gly Asn Thr Asp Tyr Asn Pro Ser Leu Lys Ser   1 5 10 15 <210> 239 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 of anti-Ang2 antibody <400> 239 Tyr Ile Asn Tyr Ser Gly Asn Thr Asp Tyr Asn Pro Ser Leu Lys Ser   1 5 10 15 <210> 240 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 240 Ser Thr Phe Gly His Tyr Val Ser Ser Met Asp Tyr   1 5 10 <210> 241 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 241 Gly Asn Phe Glu Gly Ala Met Asp Tyr   1 5 <210> 242 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 of anti-Ang2 antibody <400> 242 Gly Asp Tyr Gly Asn Tyr Val Gly Pro Met Asp Tyr   1 5 10 <210> 243 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 243 Lys Ala Ser Gln Ser Ala Ser Asn Asp Val Ala   1 5 10 <210> 244 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of anti-Ang2 antibody <400> 244 Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala   1 5 10 <210> 245 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 245 Tyr Ala Ser Asn Arg Tyr Thr   1 5 <210> 246 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 of anti-Ang2 antibody <400> 246 Tyr Ala Ser Asn Arg Tyr Pro   1 5 <210> 247 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 247 Gln Gln Asp Tyr Ser Ser Pro Thr   1 5 <210> 248 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 248 Gln Gln Asp Tyr Thr Ser Pro Trp Thr   1 5 <210> 249 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 249 Gln Gln Asp Tyr Ser Ser Pro Leu Thr   1 5 <210> 250 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 250 Gln Gln Asp Tyr Arg Ser Pro Trp Thr   1 5 <210> 251 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 of anti-Ang2 antibody <400> 251 Gln Gln Asp Tyr Ser Ser Pro Trp Thr   1 5 <210> 252 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 252 Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser   1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr              20 25 30 Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met          35 40 45 Gly Tyr Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Su      50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu  65 70 75 80 Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Ala                  85 90 95 Arg Ser Thr Phe Gly His Tyr Val Ser Ser Met Asp Tyr Trp Gly Gln             100 105 110 <210> 253 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 253 Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser   1 5 10 15 Leu Ser Leu Ser Cys Thr Val Thr Gly Tyr Ser Ile Ala Ser Asp Tyr              20 25 30 Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Val Glu Trp Met          35 40 45 Gly Tyr Ile Asn Tyr Arg Gly Asn Thr Asp Tyr Asn Pro Ser Leu Lys      50 55 60 Ser Arg Ser Ser Ile Asn Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu  65 70 75 80 Gln Leu Asn Ser Val Thr Thr Gly Asp Thr Ala Thr Tyr Tyr Cys Ala                  85 90 95 Arg Gly Asn Phe Gly Gly Ala Met Asp Tyr Trp Gly Gln             100 105 <210> 254 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 254 Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser   1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr              20 25 30 Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met          35 40 45 Gly Tyr Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Su      50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu  65 70 75 80 Gln Leu Asn Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala                  85 90 95 Arg Gly Asp Tyr Gly Asn Tyr Val Gly Pro Met Asp Tyr Trp Gly Gln             100 105 110 <210> 255 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 255 Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser   1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr              20 25 30 Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met          35 40 45 Gly Tyr Ile Asn Tyr Ser Gly Asn Thr Asp Tyr Asn Pro Ser Leu Lys      50 55 60 Ser Arg Ser Ser Ile Thr Arg Asn Thr Ser Lys Asn Gln Phe Phe Leu  65 70 75 80 Gln Leu Asn Ser Val Thr Thr Gly Asp Thr Ala Thr Tyr Tyr Cys Thr                  85 90 95 Arg Gly Asn Phe Glu Gly Ala Met Asp Tyr Trp             100 105 <210> 256 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain antigent binding region of anti-Ang2 antibody <400> 256 Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser   1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr              20 25 30 Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met          35 40 45 Gly Tyr Ile Asn Tyr Ser Gly Asn Thr Asp Tyr Asn Pro Ser Leu Lys      50 55 60 Ser Arg Ser Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu  65 70 75 80 Gln Leu Asn Ser Val Thr Thr Gly Asp Thr Ala Thr Tyr Tyr Cys Ala                  85 90 95 Arg Gly Asn Phe Glu Gly Ala Met Asp Tyr Trp Gly             100 105 <210> 257 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 257 Ser Ile Val Met Thr Gln Thr Pro Lys Leu Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Ala Ser Asn Asp              20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Ala Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Ile Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Pro                  85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 258 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 258 Thr Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Ile Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp              20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Pro Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Trp                  85 90 95 Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys             100 105 <210> 259 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 259 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp              20 25 30 Val Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Leu                  85 90 95 Thr Phe Gly Ala Arg Thr Lys Leu Glu Leu Lys             100 105 <210> 260 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 260 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp              20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Pro Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Arg Ser Pro Trp                  85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 261 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain antigent binding region of anti-Ang2 antibody <400> 261 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly   1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp              20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile          35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Pro Gly Val Pro Asp Arg Phe Thr Gly      50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala  65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Trp                  85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 262 <211> 1527 <212> DNA <213> Artificial Sequence <220> Anti-Ang2 scFv-Fc, then sequences from 1st to 6th positions          and 1522nd to 1527th positions are restriction sites <400> 262 aagcttgcca ccatgggctg gagctgcatc atcctgttcc tggtggccac cgccaccggc 60 gtgcacagcc aggtgcagct ggtgcagagc ggcgccgagg tgaagaagcc cggcgccagc 120 gtgaaggtga gctgcaaggc cagcggctac accttcaccg gctactacat gcactgggtg 180 cgccaggccc ccggccaggg cctggagtgg atgggctgga tcaaccccaa cagcggcggc 240 accaactacg cccagaagtt ccagggccgc gtgaccatga cccgcgacac cagcatcagc 300 cggctgcgcc cgcagcccca acccctacta ctacgacagc agcggctact actaccccgg cgccttcgac 420 atctggggcc agggcaccat ggtgaccgtg agcggcggcg gcggcagcgg cggcggcggc 480 agcggcggcg gcggcagcca gcccggcctg acccagcccc ccagcgtgag cgtggccccc 540 ggccagaccg cccgcatcac ctgcggcggc aacaacatcg gcagcaagag cgtgcactgg 600 taccagcaga agcccggcca ggcccccgtg ctggtggtgt acgacgacag cgaccgcccc 660 agcggcatcc ccgagcgctt cagcggcagc aacagcggca acaccgccac cctgaccatc 720 agccgcgtgg aggccggcga cgaggccgac tactactgcc aggtgtggga cagcagcagc 780 gaccactacg tgttcggcac cggcaccaag gtgaccgtgc tggagcccaa atcttgtgac 840 aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggccc gtcagtcttc 900 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 960 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 1020 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 1080 gtggtcagcg tcctcaccgt cctgcaccag gactggctta atggcaagga gtacaagtgc 1140 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1200 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaagagat gaccaagaac 1260 cggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1320 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1380 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1440 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1500 tccctgtctc cgggtaaatg actcgag 1527

Claims (25)

A first polypeptide comprising a first antigen binding site;
A second polypeptide comprising a second antigen binding site; And
A linker linking said first polypeptide and said second polypeptide;
Lt; / RTI &gt;
Wherein the first antigen binding site is a single-stranded polypeptide to which the first light chain antigen binding site and the first heavy chain antigen binding site are linked,
Wherein the second antigen binding site is a single-stranded polypeptide to which a second light chain antigen binding site and a second heavy chain antigen binding site are linked,
One of the first antigen binding site of the first polypeptide and the second antigen binding site of the second polypeptide is an antigen binding site specifically binding to c-Met, and the other is an antigen binding site specifically binding to Ang-2 , &Lt; / RTI &gt;
Wherein the linker is linked to a tag that joins the C-terminus of the first polypeptide and the N-terminus of the second polypeptide and has a cleavable amino acid sequence,
Protein complex. Wherein one of the first polypeptide and the second polypeptide comprises a knob forming amino acid residue at a residue except for a first antigen binding site and a second antigen binding site, Forming amino acid residue at the site other than the antigen binding site and the second antigen binding site. 3. The protein complex of claim 2, wherein the knob is formed in the CH3 domain of the polypeptide of either the first polypeptide or the second polypeptide, and the hole is formed in the CH3 domain of the other polypeptide. . 3. The method of claim 2,
Wherein the knob forming amino acid is at least one selected from the group consisting of Arg, Phe, Tyr, and Trp,
Wherein the hole-forming amino acid is at least one selected from the group consisting of Ala, Ser, Thr, Gly, and Val.
Protein complex. The protein complex of claim 1, wherein the tag is at least one protein selected from the group consisting of ubiquitin, ubiquitin-like protein, TEV cleavage peptide, and furin cleavage peptide. 2. The protein complex of claim 1, wherein the linker is a polypeptide consisting of 1 to 100 amino acids. 2. The method according to claim 1, wherein the antigen binding site specifically binding to c-Met comprises
A CDR-H1 having the amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 2, or a sequence of 8 to 19 consecutive amino acids including the third to tenth amino acids in the amino acid sequence of SEQ ID NO: CDR-H2 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 85, or SEQ ID NO: 85, and consecutive 6 to 13 amino acids including the first to sixth amino acids in the amino acid sequence of SEQ ID NO: CDR-H3 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 3; And
CDR-L1 having the amino acid sequence of SEQ ID NO: 7, CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and amino acid sequence of SEQ ID NO: 9, SEQ ID NO: 86, or SEQ ID NO: A light chain antigen binding site comprising at least one light chain complementarity determining region selected from the group consisting of CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids including up to the 9th amino acid
&Lt; / RTI &gt; 8. The method of claim 7,
The CDR-H1 has an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24,
The CDR-H2 has an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 25, and SEQ ID NO: 26,
The CDR-H3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 85,
The CDR-L1 has an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33,
The CDR-L2 has an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36,
Wherein the CDR-L3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 13, 14, 15, 16, 39,
Protein complex. [Claim 7] The method according to claim 7, wherein the antigen binding site specifically binding to c-
A polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, an amino acid selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: (CDR-H3) comprising a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: 28 and SEQ ID NO: 85 part; And
A polypeptide (CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, (CDR-L2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36 and a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: (CDR-L3) having an amino acid sequence selected from the group consisting of SEQ ID NO: 37, SEQ ID NO: 86, and SEQ ID NO: 89.
&Lt; / RTI &gt; [Claim 7] The method according to claim 7, wherein the antigen binding site specifically binding to c-
A heavy chain antigen binding site having an amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 74, SEQ ID NO: 87, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO:
The amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 75, SEQ ID NO: 88, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: Lt; RTI ID = 0.0 &gt;
&Lt; / RTI &gt; The protein complex of claim 1, wherein the antigen binding site specifically binding to Ang-2 comprises a heavy chain binding site of SEQ ID NO: 109 and a light chain binding site of SEQ ID NO: 110. The method according to claim 1,
The antigen-binding site that specifically binds to Ang-2 is,
A polypeptide having the amino acid sequence of SEQ ID NO: 131 (CDR-H1), a polypeptide having the amino acid sequence of SEQ ID NO: 132 (CDR-H2), and a polypeptide having the amino acid sequence of SEQ ID NOs: 156 to 163 A heavy chain antigen binding site comprising at least one selected from the group consisting of: And
(CDR-L2) having the amino acid sequence of SEQ ID NO: 134 and a polypeptide (CDR-L3) having the amino acid sequence of SEQ ID NO: 135. The polypeptide having the amino acid sequence of SEQ ID NO: Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; light chain antigen binding site
&Lt; / RTI &gt; The method according to claim 1,
The antigen-binding site that specifically binds to Ang-2 is,
A polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 204 to SEQ ID NO: 207, a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 208 to 211, (CDR-H3) having an amino acid sequence selected from the group consisting of SEQ ID NOS: 212 to 215; a heavy chain antigen binding site comprising at least one selected from the group consisting of: And
(CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 to 219, a polypeptide having the amino acid sequence of SEQ ID NO: 136 (CDR-L2) Peptide (CDR-L3), which comprises at least one light chain antigen binding site
&Lt; / RTI &gt; The method according to claim 1,
The antigen-binding site that specifically binds to Ang-2 is,
A polypeptide having the amino acid sequence of SEQ ID NO: 236 (CDR-H1), a polypeptide having the amino acid sequence of SEQ ID NO: 138 (CDR-H2), and a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 240 to SEQ ID NO: Peptide (CDR-H3); a heavy chain antigen binding site comprising at least one selected from the group consisting of peptides (CDR-H3); And
A polypeptide having the amino acid sequence of SEQ ID NO: 243 or SEQ ID NO: 244 (CDR-L1), a polypeptide having the amino acid sequence of SEQ ID NO: 245 or SEQ ID NO: 246 (CDR- Peptide (CDR-L3), which comprises at least one light chain antigen binding site
&Lt; / RTI &gt; The protein complex according to claim 1, wherein the protein complex comprises the amino acid sequence of SEQ ID NO: 127, the 20th to 1066th amino acids of SEQ ID NO: 127, the amino acid sequence of SEQ ID NO: 129 and the 20th to 1066th amino acids of SEQ ID NO: 129 Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt; 17. A bispecific antibody to c-Met and Ang-2 comprising the protein complex of any one of claims 1 to 15. The protein complex according to claim 16, wherein the protein complex comprises a first polypeptide and a second polypeptide which are dimerized in the remaining part except for the first antigen binding site and the second antigen binding site, and wherein the cleavable amino acid sequence is truncated, Double specific antibody. 17. A polynucleotide encoding the protein complex of any one of claims 1 to 15. 19. The polynucleotide according to claim 18, wherein the polynucleotide has a nucleotide sequence of SEQ ID NO: 128, a nucleotide sequence from position 60 to position 3198 of SEQ ID NO: 128, a nucleotide sequence of SEQ ID NO: 130, and a nucleotide sequence from position 60 to position 3198 Wherein the polynucleotide has a base sequence selected from the group consisting of: 20. A recombinant vector comprising the polynucleotide of claim 19 and an expression regulator operatively linked to the polynucleotide. 20. Recombinant cells comprising the recombinant vector of claim 20. 15. A method of producing a bispecific antibody to c-Met and Ang-2 comprising the step of producing the protein complex of any one of claims 1 to 15. 23. The method of claim 22, further comprising, after said producing, cutting said tag. 24. The method of claim 23, wherein the cleavage is performed by adding a protease that recognizes a cleavable amino acid sequence included in the tag of the protein complex. The pharmaceutical composition according to claim 16, which comprises as an active ingredient a bispecific antibody against c-Met and Ang-2 as an active ingredient. Rheumatoid arthritis, chronic inflammation, hypertension, arteriosclerosis, and sepsis.

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