RU2793631C2 - Fusion protein containing human lefty a protein variants and its use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention is related specifically to therapeutic proteins based on the human protein Lefty A, and can be used in medicine to prevent or treat a neuromuscular disease. A variant of the human Lefty A protein was constructed containing the amino acid sequence L22 to P366 of SEQ ID NO: 131 with a substitution of one or more amino acid residues at processing sites selected from the group consisting of R74G, R77G or R77V, R132G and R135G; and replacing one or more amino acid residues in the propeptide domain selected from the group consisting of E24G, S38K, V42T, K50E, A55T, V63A and R66Q. A fusion protein with Fc or albumin was also obtained based on this human Lefty A variant.

EFFECT: invention provides for the production of variant proteins with the activity of the human Lefty A protein, which have better stability than the native human Lefty A protein and thus are expressed at high levels and produced in high yield in CHO cells.

18 cl, 23 dwg, 16 tbl, 18 ex

Description

Technical field

The present invention relates to a human Lefty A protein variant with improved productivity and stability, a fusion protein containing said protein variant, and a composition for the prevention and/or treatment of a neuromuscular disease containing the protein variant or fusion protein.

State of the art

Lefty (Left-Right Determination Factor) is a morphological differentiation factor that belongs to the transforming growth factor-beta (TGF-β) superfamily and plays a critical role in embryonic cell differentiation and development by binding to other TGF-β ligands (Shiratori H et al., Semin Cell Dev Biol 2014; 32:80-4).

Human LEFTY genes include two genes (LEFTY2 encoding the Lefty A protein and LEFTY1 encoding the Lefty B protein) that are folded by independent duplication (Gharib WH, Robinson-Rechavi M, Brief Bioinform. 2011; 12(5):436-41 ). The decoded amino acid sequences of Lefty A and Lefty B are 96% identical to each other.

The human LEFTY gene is translated into a 366 amino acid polypeptide, and the 21 amino acid N-terminal signal peptide is cleaved during translocation to the endoplasmic reticulum (ER) and finally released extracellularly as a 42 kDa proprotein. The released 42 kD Lefty protein can be processed to remove the propeptide via protease cleavage at its N-terminal cleavage site (RXXR). Unlike other members of the TGF-b family, Lefty has two putative cleavage sites instead of one (RXXR) and lacks the conserved cysteine required for homodimer formation. (Juan et al., Genes to Cells. 2001; 6:923-30).

The Lefty polypeptide can be cleaved with proprotein convertases at the carboxyl terminus of the second arginine of each cleavage site and processed into 34 kDa and 28 kDa polypeptides. Proteolytic processing of the Lefty polypeptide can be prevented by mutating both arginine residues at the first cleavage site (RGKR) to glycine or the first arginine at the second cleavage site (RHGR) to glycine (Ulloa L et al., J Biol Chem. 2001; 276:217387-96 ).

It has been reported that the 42 kDa Lefty proprotein as well as the mature 28 kDa protein can induce MAPK activation (Ulloa L et al., J Biol Chem. 2001; 276:217387-96).

Lefty acts as an endogenous Nodal inhibitor that plays an important role in early vertebrate embryonic development, such as inducing mesoderm and endoderm differentiation and controlling left-right asymmetry (Schier AF, Annu Rev Cell Biol. 2003; 19:589-621). The exact mechanism of action by which Lefty inhibits Nodal is still unclear, but it is known that Lefty can bind to Nodal and thereby prevent Nodal from binding to activin receptors (e.g., ActRI or ActRII) and the EGF-CFC co-receptor (Branford et al., Current Biol 2004; 14:341-3 and Chen et al Current Biol 2004; 14:618-24). In addition, Lefty has been reported to inhibit TGF-β or BMP signaling (Ulloa L et al., J Biol Chem. 2001; 276(24): 21397-404).

There are a number of TGF-β superfamily ligands such as bone morphogenetic proteins (BMP), growth and differentiation factor (GDF), Nodal, activin and TGF-β. They play an important role in the regulation of embryonic development and the function of many cells and organs after birth. For example, members of the TGF-β family are involved in neuronal differentiation and regulate various parts of the central nervous system at all stages of development, from early embryos to adults (Myers EA and Kessler JA, Cold Spring Harb Perspect Biol. 2017; 9(8)). TGF-β inhibits the survival of Schwann cells during neuronal differentiation (Parkinson et al., J Neurosci. 2001; 21:8572-85). BMP7 inhibits the Schwann cell myelination process by activating p38 in the peripheral nerve (Liu X et al., Sci Rep. 2016; 6:31049). GDF8 (myostatin) inhibits skeletal muscle growth and its overexpression causes skeletal muscle atrophy (Elkina Y et al., J Cachexia Sarcopenia Muscle. 2001; 2:143-51).

Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary peripheral neuropathies with a prevalence of 1 in 2500. More than 80 genes that cause CMT have been identified Patients with CMT develop slowly progressive muscle atrophy and sensory loss that begins in the lower extremities.

CMT is a phenotypically and genetically heterogeneous disease and is divided into demyelinating type (CMT1) and axonal type (CMT2) based on upper limb motor nerve conduction velocities (MNCVs). Among these types, the demyelinating type (CMT1) accounts for approximately 70% of all CMT patients and is caused by overexpression or mutation of myelin proteins such as PMP22 and MPZ. Although the pathophysiological mechanisms have not been elucidated, it is hypothesized that ER stress is caused by protein overexpression or mutation, followed by Schwann cell apoptosis as one of the mechanisms. Since there are no approved drugs for the treatment of CMT, interest in the development of effective therapeutic agents for the treatment of CMT is increasing.

Based on this prior art, the present inventors have engineered a variant with increased productivity and stability by introducing a mutation in the human Lefty A protein to allow the Lefty A protein to be solubilized to treat neuropathy or muscle disease, thereby completing the present invention.

The information disclosed in the Background section is only intended to facilitate understanding of the background of the present invention and, therefore, may not contain information that constitutes prior art that would already be known to a person skilled in the art.

Disclosure of invention

Technical task

It is an object of the present invention to provide a variant of the human Lefty A protein with increased productivity and stability.

Another object of the present invention is to provide a fusion protein containing the human Lefty A variant.

Another object of the present invention is to provide a nucleic acid molecule encoding a fusion protein, an expression vector containing the nucleic acid molecule, a recombinant cell into which the expression vector has been introduced, and a method for producing a fusion protein using the recombinant cell.

Another object of the present invention is to provide a composition for the prevention and/or treatment of a neuromuscular disease that contains either a protein variant or a fusion protein.

Another object of the present invention is to provide a method for preventing and/or treating a neuromuscular disease which comprises administering to a subject either a protein variant or a fusion protein.

Yet another object of the present invention is to provide the use of a protein variant or fusion protein for the prevention and/or treatment of a neuromuscular disease.

Yet another object of the present invention is to provide the use of either a protein variant or a fusion protein in the manufacture of a medicament for the treatment of a neuromuscular disease.

Technical solution

To achieve the above objects, the present invention provides a human Lefty A protein variant comprising the amino acid sequence L22-P366 of the human Lefty A protein having the amino acid sequence of SEQ ID NO: 131, wherein the human Lefty A protein variant comprises: (1) a substitution of one or more amino acid residues at processing sites (R74-R77 and R132-R135); and (2) substitution of one or more amino acid residues in the propeptide domain (L22-S73).

The present invention also relates to a fusion protein containing the human Lefty A variant.

The present invention also provides a nucleic acid molecule encoding a fusion protein containing a human Lefty A variant protein, an expression vector containing the nucleic acid molecule, a recombinant cell into which the expression vector has been introduced, and a method for producing a fusion protein containing a human Lefty A variant protein. using recombinant cells.

The present invention also provides a composition for the prevention and/or treatment of a neuromuscular disease that comprises either a human Lefty A protein variant or a fusion protein containing a human Lefty A protein variant.

The present invention also provides a method for preventing and/or treating a neuromuscular disease which comprises administering either a human Lefty A protein variant or a fusion protein containing a human Lefty A protein variant.

The present invention also provides the use of either a human Lefty A variant or a fusion protein containing a human Lefty A variant in the prevention and/or treatment of neuromuscular disease.

The present invention also provides the use of either a human Lefty A variant or a fusion protein containing a human Lefty A variant in the manufacture of a medicament for the treatment of neuromuscular disease.

Brief description of the drawings

FIG. 1 is a schematic diagram of Lefty A human fusion proteins.

FIG. Figure 2 shows Western blot analysis of culture supernatants to assess the expression of human serum albumin (HSA) fused variants of the human Lefty A protein.

FIG. 3 shows SDS-PAGE analysis of the 42 LFc protein after ProA affinity purification.

FIG. 4 shows SDS-PAGE and SEC analysis of Lefty A (combination) protein variants after ProA affinity purification.

FIG. 5 shows cell viability analysis and Western blot analysis with anti-PARP antibody (poly(ADP-ribose) polymerase) to assess the effects of co-cultivation with human mesenchymal stem cells (MSCs) obtained from Wharton's jelly on apoptosis of S16 Schwann cells induced by thapsigargin.

FIG. 6 shows an electrophysiological evaluation of the therapeutic effects of human Lefty A fusion protein variants in Tr-J mice.

FIG. Figure 7 shows a Western blot to assess the expression of KROX20 and myelin basic protein (MBP) (A) or Krox20 and phosphorylated/unphosphorylated p38 (B) in RT4 Schwann cells treated with Nodal and/or human fusion protein variant. Lefty A.

FIG. 8 shows an electrophysiological evaluation of the therapeutic effects of intraperitoneal injection of the Lefty A human fusion protein variant in C22 mice.

FIG. 9 shows rotatable rod (A) and hindlimb grip strength (B) tests in C22 mice injected intraperitoneally with the human fusion protein Lefty A variant.

FIG. 10 shows an MRI analysis of the gastrocnemius muscle of C22 mice injected intraperitoneally with the human fusion protein Lefty A variant.

FIG. 11 shows a gait analysis of wild-type and C22 mice injected intraperitoneally with the Lefty A human fusion protein variant.

FIG. 12 shows an electrophysiological evaluation of the therapeutic effects of intraperitoneal injection of the Lefty A human fusion protein variant in C22 mice.

FIG. 13 shows hindlimb (A) and rotator shaft (B) grip strength tests in C22 mice injected intraperitoneally with the Lefty A human fusion protein variant.

FIG. 14 shows a gait analysis of C22 mice injected intraperitoneally with the human Lefty A fusion protein variant.

FIG. 15 shows the electrophysiological analysis in C22 mice injected subcutaneously with the human Lefty A fusion protein variant for 4 weeks starting at 3 weeks of age.

FIG. 16 shows a test of hindlimb grip strength in C22 mice injected subcutaneously with the human Lefty A fusion protein variant for 4 weeks starting at 3 weeks of age.

FIG. 17 shows a luciferase reporter gene analysis from A204 cells to evaluate the effect of the human Lefty A fusion protein variant on myostatin signaling.

FIG. 18 shows Western blot analysis of sciatic nerve lysates from C22 mice injected with the human Lefty A fusion protein variant.

FIG. 19 shows the electrophysiological analysis in C22 mice injected subcutaneously with the human Lefty A fusion protein variant for 4 weeks starting at 5 weeks of age. 3

FIG. 20 shows rotatable rod (A) and all-limb grip force (B) tests in C22 mice injected subcutaneously with the human Lefty A fusion protein variant for 4 weeks starting at 5 weeks of age.

FIG. 21 shows a Western blot analysis to evaluate the effect of human fusion protein variant Lefty A on Nodal-induced signaling in P19 cells.

FIG. 22 and 23 show the amino acid sequences of human Lefty A fusion protein variants of the present invention.

Best Mode for Carrying Out the Invention

Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as is commonly understood by one of ordinary skill in the art to which the invention pertains. The nomenclature commonly used herein and the experimental methods to be described below are well known and commonly used in the art.

In the present invention, a fusion protein containing a variant of the human Lefty A protein (Uniprot No. 000292; NCBI DB NM_003240) with increased productivity and stability has improved productivity and stability in CHO cells compared to the wild-type protein, and it was previously reported that human Lefty variants It also binds to human Nodal and inhibits Nodal-mediated signaling, which may improve symptoms of peripheral neuropathy. Thus, the fusion protein can be effectively used alone or in combination with a conventional pharmaceutically acceptable carrier, a neuropathy therapeutic agent, a muscle disease therapeutic agent, and the like. as a composition for the prevention or treatment of neuropathy and muscle diseases.

Thus, in one aspect, the present invention is directed to a human Lefty A protein variant comprising the amino acid sequence L22-P366 of a human Lefty A protein having the amino acid sequence of SEQ ID NO: 131, wherein the human Lefty A protein variant comprises: (1) a replacement of one or more amino acid residues at processing sites (R74-R77 and R132-R135); and (2) substitution of one or more amino acid residues in the propeptide domain (L22-S73).

M1 to A21 in the human Lefty A protein having the amino acid sequence of SEQ ID NO: 131 corresponds to the signal peptide.

The human Lefty A variant of the present invention is also intended to include variants in which amino acid residues at certain amino acid residue positions are conservatively substituted.

As used herein, the term "conservative substitution" refers to modifications to the Lefty A protein variant that involve the replacement of one or more amino acids with amino acids having similar biochemical properties that do not result in loss of biological or biochemical function of the Lefty A protein variant.

A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been identified and are well known in the field to which the present invention pertains. These families include amino acids (eg, lysine, arginine, and histidine) with basic side chains, amino acids (eg, aspartic acid and glutamic acid) with acidic side chains, amino acids (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, and cysteine ) with uncharged polar side chains, amino acids (for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan) with non-polar side chains, amino acids (for example, threonine, valine, and isoleucine) with beta-branched side chains, and amino acids (eg tyrosine, phenylalanine, tryptophan and histidine) with aromatic side chains.

It is contemplated that the Lefty A protein variant of the present invention may still be active although it has conservative amino acid substitutions.

In addition, the human Lefty A protein variant of the present invention is interpreted to include a Lefty A protein variant having substantially the same function and/or effect as the Lefty A protein variant of the present invention and having an amino acid sequence homology of at least 80% or 85%, preferably at least 90%, more preferably at least 95%, most preferably at least 99%, with the Lefty A protein variant of the present invention.

Preferably, the human Lefty A protein variant of the present invention may comprise the L22-P366 amino acid sequence of any sequence selected from the group consisting of SEQ ID NO: 86 to SEQ ID NO: 111, or the L23-P367 amino acid sequence of any of the sequences selected from the group consisting of SEQ ID NO: 112 to 129 and 133, but not limited to.

It should be understood that the Lefty A protein variant of the present invention also includes those that have essentially the same effect as the Lefty A protein variant of the present invention, even though some amino acid residues at the N-terminus, C-terminus or its internal amino acid sequence is cleaved or replaced.

Lefty A wild-type mutations, ie, amino acid substitutions at positions R74-R77, are absent, and thus, when protease-induced cleavage of the corresponding region occurs, a 34 kD Lefty A protein fragment is obtained. In addition, there are no mutations at positions R132-R135, and thus when protease-induced cleavage of the corresponding region occurs, a 28 kD Lefty A protein fragment is obtained.

Accordingly, the human Lefty A variant of the present invention preferably comprises a substitution of one or more amino acids at the processing sites consisting of R74-R77 and R132-R135.

In the present invention, the substitution of amino acid residues in the propeptide domain (L22-S73) may be a substitution of amino acid residues at one or more positions selected from the group consisting of: E24, L27, R33, S38, V40, V42, R45, M48, K50 , A55, V63, R66, R67, G70 and D71, but not limited to.

Preferably, the substitution of amino acid residues in the propeptide domain (L22-S73) may be one or more amino acid residue substitutions selected from the group consisting of: E24G, S38K, V42T, K50E, A55T, V63A and R66Q.

Most preferably, the substitution of amino acid residues in the propeptide domain (L22-S73) may include V63A and may additionally include one or more amino acid residue substitutions selected from the group consisting of: E24G, S38K, V42T, K50E, A55T and R66Q.

In the present invention, a substitution of one or more amino acid residues at processing sites (R74-R77 and R132-R135) may be a substitution of one or more amino acid residues selected from the group consisting of: R74G, R77G, R77V, R132G and R135G.

The amino acid sequence of positions R74-R77 may be RGKR, GGKG, RGKA, RGKV, or RHGG, and the amino acid sequence of positions R132-R135 may be RHGR, GHGR, RHGG, RHER, GHGG, RHGA, or RHGV, which are the result of a substitution of one or more amino acid residues at processing sites (R74-R77 and R132-R135).

In the present invention, the human Lefty A protein variant may further include, but is not limited to, replacing one or more amino acid residues at the thrombin cleavage site (L311, P313, R314, L359, P361, or R362).

Preferably, amino acid residues at one or more positions selected from the group consisting of thrombin cleavage sites L311, P313, R314, L359, P361 and R362 may be replaced by amino acid residues selected from the group consisting of aspartic acid (D), glutamic acid (E), serine (S), lysine (K), and glutamine (Q).

In the present invention, the human Lefty A variant may further comprise replacing one or more amino acid residues at the fragmentation site (S202 or S223) with amino acid residues other than serine (S) and cysteine (C).

In the present invention, the human Lefty A variant may further comprise a signal peptide at the N-terminus.

(UniProt: A0A0C4DH73; SEQ ID NO: 132), но не ограничивается этим.As used herein, a signal peptide is used in the same sense as a signal sequence and is a short amino acid sequence that plays an important role in allowing a newly expressed polypeptide to target the endoplasmic reticulum and enter the secretory pathway. When the protein is synthesized in the cell and leaves the cell, the signal sequence is cleaved and the N-terminus of the Lefty A protein variant starts at L22. The signal sequence that is used in the present invention may be a signal sequence (M1-A21) derived from the Lefty A protein, but is not limited to this. It is also possible to use a signal sequence derived from a protein other than the Lefty A protein, which may be, for example, a sequence derived from an antibody, such as

(UniProt: A0A0C4DH73; SEQ ID NO: 132), but is not limited to this.

In another aspect, the present invention is directed to a fusion protein comprising the human Lefty A variant.

In the present invention, "fusion protein containing the Lefty A variant protein" is used in the same sense as "Lefty A fusion protein variant".

In the present invention, the fusion protein can be obtained by fusion of the human Lefty A variant protein with Fc or albumin, but is not limited to this.

Preferably, the fusion protein of the present invention can be obtained by fusion of Fc or albumin to the N-terminus or C-terminus, preferably to the C-terminus of the Lefty A human protein variant. Lefty A protein with Fc or albumin through a linker.

Fc in the present invention refers to the Fc (crystallizing fragment) region of an antibody and may be an Fc of an antibody selected from the group consisting of: IgG, IgA, IgM and IgE. Preferably, it may be an Fc of an antibody selected from, but not limited to, human IgG, IgA, IgM, and IgE.

More preferably, the Fc may be selected from, but not limited to, human IgG1, IgG2, IgG3, and IgG4, which are derived from human IgG, and most preferably, it may be an Fc derived from human IgG1. In addition, the Fc in the present invention may be a wild-type Fc or a variant of its amino acid sequence.

In addition, albumin in the present invention includes all albumins of animal origin. Preferably, human albumin may be used, but the scope of the present invention is not limited thereto.

In the present invention, the fusion protein may have any one amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs: 134-178, but is not limited to them.

In the present invention, the amino acid sequences shown in SEQ ID NO: 134-159 refer to the amino acid sequences L22-K614, except for the signal sequence in the amino acid sequences shown in SEQ ID NO: 86-SEQ ID NO: 111, respectively. The amino acid sequences shown in SEQ ID NO: 160-178 refer to the amino acid sequences L23-K615, except for the signal sequence in the amino acid sequences shown in SEQ ID NO: 112-129 and SEQ ID NO: 133, respectively (FIG. 22a- 22j and FIGS 23a-23m).

(UniProt: A0A0C4DH73; SEQ ID NO: 132), но не ограничивается этим.The fusion protein of the present invention may further comprise a signal peptide at the N-terminus. The signal peptide capable of binding to the N-terminus of the fusion protein may be a signal sequence (M1-A21) derived from the Lefty A protein, similar to, but not limited to, the human Lefty A protein variant. The signal peptide that is used in the present invention may be a signal sequence derived from a protein other than the Lefty A protein, for example, an antibody-derived sequence such as

(UniProt: A0A0C4DH73; SEQ ID NO: 132), but is not limited to this.

In yet another aspect, the present invention is directed to a nucleic acid molecule encoding a fusion protein, an expression vector containing the nucleic acid molecule, a recombinant cell into which the expression vector has been introduced, and a method for producing a fusion protein containing the human Lefty A variant protein using the recombinant cell. .

As used herein, the term "nucleic acid molecule" is meant to encompass DNA (gDNA and cDNA) and RNA molecules in its entirety, and the nucleotide, which is the basic unit of the nucleic acid molecule, also includes sugar or base-modified analogs, as well as the natural nucleotide (Scheit, Nucleotide Analogs, John Wiley, New York (1980); Uhlman and Peyman, Chemical Reviews 1990; 90:543-84). The sequence of the nucleic acid molecule encoding the human fusion protein Lefty A variant of the present invention may be modified. The modification includes the addition, deletion or non-conservative substitution or conservative substitution of nucleotides.

As used herein, the term "vector" includes a plasmid vector; cosmid vector; bacteriophage vector; and a viral vector, such as an adenoviral vector, retroviral vectors, and adeno-associated viral vectors, as a means of expressing a target gene in a host cell. Preferably, the vector may include, but is not limited to, a plasmid vector.

A nucleic acid molecule encoding a fusion protein containing the human Lefty A variant in the vector of the present invention may be operably linked to a promoter.

As used herein, the term "operably linked" refers to a functional relationship between a nucleic acid expression control sequence (e.g., a promoter sequence, a signal sequence, or a transcription regulatory factor binding site) and another nucleic acid sequence, and thus the control sequence controls transcription and /or translation of another nucleic acid sequence.

The recombinant vector system of the present invention can be constructed by various methods known in the art, and a detailed method is described in Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press (2001), which is incorporated herein by reference. .

The vector can usually be designed as a cloning vector or an expression vector. The vector can be designed as a vector that uses a prokaryotic cell or a eukaryotic cell as a host.

For example, when the vector of the present invention is an expression vector and a prokaryotic cell is used as a host cell, a strong promoter capable of stimulating transcription is generally included (such as tac promoter, lac promoter, lacUV5 promoter, lpp promoter, pLλ promoter, pRλ promoter , rac5 promoter, amp promoter, recA promoter, SP6 promoter, trp promoter, T7 promoter, etc.), a ribosome binding site for translation initiation, and a transcription/translation termination sequence. When E. coli such as HB101, BL21, DH5α and the like is used as the host cell, E. coli tryptophan biosynthesis operator and promoter (Yanofsky, C., J. Bacteriol., (1984) 158:1018 -1024) and the left phage λ promoter (promoter pLλ, Herskowitz, I. and Hagen, D., Ann. Rev. Genet., (1980) 14:399-445) can be used as a regulatory sequence. When bacilli are used as host cells, a toxin (protein) gene promoter from bacillus thuringiensis (Appl. Environ. Microbiol. (1998) 64:3932-3938; Mol. Gen. Genet. (1996) 250:734-741) or any promoters that can be expressed in bacilli can be used as a regulatory sequence.

Meanwhile, the expression vector according to the present invention can be constructed by manipulating plasmids (e.g., pCL, pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8/9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14, pGEX series, pET series, pUC19, etc.), phages (e.g. λgt⋅4λB, λ-Charon, λΔz1, M13, etc.) or viruses (e.g. SV40, etc.) that are normally used in this field of technology. For example, the expression vector according to the present invention can be constructed by manipulating the expression vector pCL, in particular the expression vector pCLS05 (Korean Patent Registration No. 10-1420274), but not limited to this.

In addition, when the vector of the present invention is an expression vector and a eukaryotic cell is used as the host cell, promoters derived from the genomes of mammalian cells (for example, metallothionein promoter, β-actin promoter, human hemoglobin promoter, and human muscle creatinine promoter) can be used. ), or promoters derived from mammalian viruses (e.g. adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus (CMV) promoter, HSV tk promoter, mouse mammary tumor virus (MMTV) promoter, HIV LTR promoter, Moloney virus promoter, Epstein-Barr virus (EBV) promoter and Rous sarcoma virus (RSV) promoter.And the vector usually includes a polyadenylated sequence as a transcription termination sequence.Specifically, the recombinant vector according to the present invention includes a CMV promoter.

The recombinant vector of the present invention can be fused with another sequence to facilitate purification of the recombinant protein expressed from it. The fusion sequence includes, for example, glutathione S-transferase (Pharmacia, USA), maltose binding protein (NEB, USA), FLAG (IBI, USA), 6x His (hexahistidine; Quiagen, USA) and the like. In addition, since Fc is fused to the protein expressed by the vector of the present invention, the expressed protein can be easily purified using a protein A column or the like without requiring additional purification sequence.

Meanwhile, the recombinant vector of the present invention includes an antibiotic resistance gene commonly used in the art as a selectable marker, and may include, for example, genes having resistance to ampicillin, gentamicin carbenicillin, chloramphenicol, streptomycin, kanamycin, geneticin, neomycin and tetracycline.

A recombinant cell that is capable of stably and consistently cloning and expressing the vector of the present invention can be used as any host cell known in the art. The host cell includes a prokaryotic host cell such as, for example, a strain belonging to the genus Bacillus, such as Escherichia coli, Bacillus subtilis and Bacillus thuringiensis, Streptomyces, Pseudomonas (for example, Pseudomonas putida), Proteus mirabilis, and Staphylococcus (for example, Staphylococcus carnosus ), but is not limited to this.

Eukaryotic host cells suitable for use with the vector include fungi such as Aspergillus sp. and yeasts such as Pichia pastoris, Saccharomyces cerevisiae, Schizosaccharomyces and Neurospora crassa and other lower eukaryotic cells and higher eukaryotic cells such as derived from insects; and cells derived from plants and mammals.

In particular, the host cells may be monkey kidney (COS7) cells, NSO cells, SP2/0 cells, Chinese hamster ovary (CHO) cells, W138, baby hamster kidney (BHK) cells, MDCK, myeloma cells, HuT 78 cells, or HEK293 cells.

The use of microorganisms such as E. coli provides higher productivity than animal cells and the like, but is not preferred for protein production due to problems such as disulfide bonding or glycosylation. However, this microorganism can be used for in vivo drug stability improvement production by PEGylation or the like.

In the present invention, transfection or transformation into a host cell includes any method by which nucleic acids can be introduced into organisms, cells, tissues or organs, and, as is known in the art, can be carried out using a suitable standard technique selected in according to the host cell type. These methods include, but are not limited to, electroporation, protoplast fusion, calcium phosphate precipitation (CaPO ₄ ), calcium chloride precipitation (CaCl ₂ ), mixing with silicon carbide fiber, and transformation mediated by agrobacteria, PEG-, dextran sulfate, lipofectamine, and loss moisture/inhibition.

The present invention provides a method for producing a recombinant protein using a recombinant cell. In particular, the method may be a method for producing a human Lefty A fusion protein variant comprising the steps of: (a) culturing a recombinant cell transformed with a recombinant vector of the present invention; and (b) expressing the recombinant protein in the recombinant cell.

The culture step in obtaining the recombinant protein can be performed using a suitable medium and culture conditions known in the art. One skilled in the art will readily be able to change the culture conditions to suit the particular strains chosen. These culture methods are disclosed in various documents (eg, James M. Lee, Biochemical Engineering, Prentice-Hall International Editions, 138-176). Cell culturing methods can be divided into suspension culture and adherent culture according to the cell growth mode, as well as batch method, fed-batch method and continuous method according to the culture mode. The culture medium used should be chosen to suit the conditions required for the specific strains used.

In animal cell culture, the medium includes a carbon source, a nitrogen source, and a trace element component. Examples of the carbon source that can be used in the present invention include carbohydrates such as glucose, sucrose, lactose, fructose, maltose, starch and cellulose, fat such as soybean oil, sunflower seed oil, castor oil and coconut oil, fatty acids, such as palmitic acid, stearic acid and linoleic acid, an alcohol such as glycerol and ethanol, and an organic acid such as acetic acid. These carbon sources can be used alone or in combination of two or more of them.

The nitrogen source that can be used in the present invention includes, for example, an organic nitrogen source such as peptone, yeast extract, meat extract (gravy), malt extract, corn syrup (CSL) and soybean meal powder, as well as an inorganic nitrogen source, such as urea, ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium carbonate and ammonium nitrate, and these nitrogen sources can be used alone or in combination of two or more of them. The medium may include, as a source of phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, and their corresponding sodium salts. In addition, metal salts such as magnesium sulfate or iron sulfate can be included in the medium as a source of phosphate. In addition, amino acids, vitamins and corresponding precursors may be included in the medium.

During cell culture, the pH of the cell culture medium can be adjusted by adding compounds such as ammonium hydroxide, potassium hydroxide, ammonia, phosphoric acid, and sulfuric acid to the culture medium in a suitable manner. In addition, an antifoam agent such as a fatty acid polyglycol ester can be used during the culture process to suppress bubble generation. In addition, oxygen or an oxygen-containing gas (eg, air) is introduced into the culture medium to keep the culture aerobic. The temperature of the culture is usually from 20°C to 45°C, preferably from 25°C to 40°C.

The recombinant protein obtained by culturing the transformed recombinant cell can be used without purification or can be used after it has been purified to a high degree of purity by various conventional methods such as dialysis, salting out and chromatography. Among these methods, the chromatography-based method is most commonly used, and the type and sequence of chromatography can be selected from ion exchange chromatography, size exclusion chromatography, affinity chromatography, and the like, depending on the characteristics of the recombinant protein, the culture method, etc.

In yet another aspect, the present invention is directed to a composition for the prevention and/or treatment of a neuromuscular disease that comprises either a human Lefty A protein variant or a fusion protein.

In a further aspect, the present invention is directed to a method for preventing and/or treating a neuromuscular disease which comprises administering to a subject either a human Lefty A protein variant or a fusion protein comprising a human Lefty A protein variant.

In yet another additional aspect, the present invention is directed to the use of either a human Lefty A protein variant or a fusion protein containing a human Lefty A protein variant for the prevention and/or treatment of a neuromuscular disease.

In yet another additional aspect, the present invention is directed to the use of either a human Lefty A variant or a fusion protein containing a human Lefty A variant in the manufacture of a medicament for the treatment of neuromuscular disease.

As used herein, the term "prevent/prevent" means any action that inhibits or delays the development of diseases, such as a neuromuscular disease and the like, by administering a composition of the present invention, and "treat/treatment" means suppressing the development, alleviating or elimination of diseases such as neuromuscular diseases and the like.

In one example of the present invention, it was confirmed that a fusion protein containing the human Lefty A variant of the present invention can bind to human Nodal and inhibit Nodal-induced signaling, thus improving parameters associated with peripheral neuropathy. In addition, in one example of the present invention, it was confirmed that the Lefty A human fusion protein variant can inhibit myostatin signaling in a dose-dependent manner. In addition, it has been found that the human Lefty A fusion protein variant can block signaling of p38, a negative regulator of myelination, and thus can be used as a treatment for peripheral neuropathy, especially demyelination-induced neuropathy.

Therefore, in the present invention, the neuromuscular disease may be a disease originating in peripheral nerves or muscles, preferably a disease associated with the Nodal and/or myostatin signaling pathways, but not limited to this. The disease associated with Nodal and/or myostatin signaling pathways may be myopathy, peripheral neuropathy, or stiff spine syndrome.

Myopathy may be selected from the group consisting of: sarcopenia, muscular dystrophy, myasthenia gravis, amyotrophic lateral sclerosis (or Lou Gehrig's disease), primary lateral sclerosis, progressive muscular atrophy, Kennedy's disease (or spinobulbar muscular atrophy), spinal muscular atrophy, and distal myopathy.

Peripheral neuropathy may be selected from the group consisting of: Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, carpal tunnel syndrome, diabetic peripheral neuropathy, and Guillain-Barré syndrome.

The composition may be provided in the form of a pharmaceutical composition, a quasi-drug composition, or a health functional food composition.

The composition for preventing or treating a disease according to the present invention may further comprise a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not impair the biological activity and characteristics of the administered compound without irritating the body. As a pharmaceutically acceptable carrier in a composition prepared as a liquid solution, a sterile and biocompatible carrier is used. The pharmaceutically acceptable carrier may be saline, sterile water, buffered saline, albumin injection, dextrose, maltodextrin, glycerin, or a mixture of two or more of these. In addition, the composition according to the present invention may, if necessary, contain other conventional additives, including antioxidants, buffers and bacteriostatic agents. In addition, the composition according to the present invention can be prepared in the form of injection forms, such as aqueous solutions, suspensions or emulsions, using diluents, dispersants, surfactants, binders and lubricants. In addition, the composition according to the present invention may be in the form of pills, capsules, granules or tablets.

The pharmaceutical composition according to the present invention may be formulated into an oral or parenteral dosage form. The pharmaceutical composition according to the present invention is prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants or surfactants that are commonly used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. Such solid formulations are prepared by mixing one or more compounds with at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple combinations, lubricants such as magnesium stearate, talc, etc. may also be added. Liquid formulations for oral administration, such as suspensions, internal solutions, emulsions, syrups, etc., may include simple diluents, such as water and liquid paraffin, as well as various excipients, such as wetting agents, sweeteners, flavors, preservatives, etc. .d. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, and suppositories. Non-aqueous solvents and suspensions can be prepared using propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate. Witepsol, macrogol, tween 61, cocoa fat, lauric fat, glycerogelatin, etc. can be used as the basis for suppositories.

Pharmaceutically acceptable carriers and formulations are detailed in Remington's Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition according to the present invention can be administered orally or parenterally. Parenteral administration is carried out by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, and the like. For oral administration, the active ingredient in the compositions must be formulated into a coated dosage form or into a dosage form that can be protected by the active ingredient from degradation in the stomach, given that peptides and proteins are digested in the stomach. Alternatively, the composition according to the present invention can be administered through any device by which the active ingredient can be transported to the target cell of interest.

A suitable dosage of the composition for preventing or treating a disease according to the present invention may vary depending on such factors as preparation method, route of administration, age of the patient, body weight, sex, pathological condition, nutrition, time of administration, route of administration, rate of elimination and allergic reaction. . Thus, the general practitioner can readily determine and prescribe a dosage effective for the desired treatment or prevention of the disease of interest.

According to one embodiment of the present invention, the daily dosage of the pharmaceutical composition according to the present invention may be from 0.001 mg/kg to 100 mg/kg. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to prevent, treat, and diagnose diseases such as neuromuscular disease and the like.

A composition for the prevention or treatment of a disease according to the present invention may be prepared using a pharmaceutically acceptable carrier and/or excipient in accordance with a method that can be easily carried out by those skilled in the art to which the present invention pertains, such that it should be provided in unit dosage form or placed in multi-dose vials. As used herein, the formulations may be in the form of solutions, suspensions, or emulsions in oils or aqueous media, or in the form of extracts, grains, suppositories, powders, granules, tablets, or capsules, and may additionally include dispersing or stabilizing agents.

Preferably, the composition of the present invention may be in an injectable form, in which case the injectable composition may be either a reconstituted lyophilized composition or a liquid composition presented in a ready-for-injection (RTI) form, but is not limited thereto.

The composition of the present invention may be administered in the form of a single therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent.

Examples

Hereinafter, the present invention will be described in more detail with reference to examples. It will be apparent to a person skilled in the art that these examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention.

Example 1: Construction of Human Fusion Proteins Lefty A

Example 1-1: Construction of Human Protein Variants Lefty A

The amino acid sequence of the human wild-type Lefty A protein is as follows:

In the amino acid sequence, M1-A21 corresponds to the signal peptide sequence, L22-S73 corresponds to the propeptide domain, and R74-R77 and R132-R135 correspond to processing sites.

The human wild-type Lefty A protein is pre-processed in the 42 kD form, but is processed to the 34 kD or 28 kD form while the region containing the propeptide domain is removed by proprotein convertases. To elucidate the function of these three forms of the protein fragment, 42, 34, and 28 kDa protein expression vectors were constructed.

For proteins of the 42 kDa and 34 kDa form, processing site mutations (42: R74G/R77G/R132G, 34: R132G) were introduced during construction to prevent further cleavage (THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 276, No. 24, Issue of June 15, pp. 21387-21396, 2001). Human Lefty A fragment 42 (L22-P366, R74G/R77G/R132G), fragment 34 (F78-P366, R132G) and fragment 28 (L136-P366) were synthesized by Bioneer Co., Ltd. (Korea) and used as templates for PCR. Using the primer pair L1_F (SEQ ID NO: 13) and L2_R (SEQ ID NO: 14) and the ProFlex system (Applied Biosystems, USA), the amplification process was carried out with Ex taq (Takara, Japan) according to the manufacturer's instructions under the following conditions , thereby obtaining fragments of human Lefty A 42, 34 and 28: 22 cycles, each of which consists of denaturation at 95°C for 60 sec, primer annealing at 58°C for 60 sec and extension at 72°C for 60 sec.

Example 1-2: Construction of fusion proteins containing Fc at the C-terminus

Three fusion protein expression vectors containing Fc at the C-terminus (42 Fc (SEQ ID NO: 1), 34 Fc (SEQ ID NO: 2) and 28 Fc (SEQ ID NO: 3)) were constructed by linking human IgG1 Fc with variants of the human Lefty A protein from Example 1-1. 28 Fc, 34 Fc, and 42 Fc mean that Fc is fused at the C-terminus of each of the 28, 34, and 42 kD Lefty A proteins.

Using DNA encoding a human IgG1 sequence (Uniprot: P01857) as a template and primer pair L3_F (SEQ ID NO: 15) and L4_R (SEQ ID NO: 16), amplification was performed under the same conditions as those used for PCR amplification of human Lefty A fragments to obtain human IgG1 fragments. The obtained PCR products were separated and purified by electrophoresis in 1.5% agarose gel, and then subjected to the PCR assembly reaction under the same conditions. The resulting reaction products were separated and purified by electrophoresis in 1.5% agarose gel, and then digested with restriction enzymes Hind III and Xho I (NEB, USA). Each of the cleavage products was ligated into pCLS05 vector (Korean Patent Application No. 2011-0056685) digested with restriction enzymes Hind III and Xho I at 25° C. for 60 minutes, and then the ligation products were transformed into E. coli DH5α. Transformed cells were cultured overnight in LB medium containing 100 μg/ml ampicillin, and plasmids were extracted from the resulting colonies and then sequenced using Cosmo Genetech Co., Ltd. service. (Korea), thereby confirming that three fusion protein expression vectors containing Fc at the C-terminus were constructed.

Example 1-3: Construction of fusion proteins containing a linked Fc at the C-terminus

(SEQ ID NO: 130). 28 LFc, 34 LFc и 42 LFc означают, что Fc слит на С-конце каждого из 28, 34 и 42 кДа белков Lefty А через линкер.Three fusion protein expression vectors containing a linked Fc at the C-terminus (42 LFc (SEQ ID NO: 4), 34 LFc (SEQ ID NO: 5) and 28 LFc (SEQ ID NO: 6)) were constructed by binding of human IgG1 Fc to human Lefty A via a linker

(SEQ ID NO: 130). 28 LFc, 34 LFc and 42 LFc mean that Fc is fused at the C-terminus of each of the 28, 34 and 42 kD Lefty A proteins via a linker.

Human Lefty A 42, 34 and 28 fragments were generated in the same manner as described for the construction of fusion protein expression vectors containing an Fc at the C-terminus. For the Fc linker fragments, using the DNA encoding the sequence of human IgG1 (Uniprot: P01857) as template and primer pair L5_F (SEQ ID NO: 17) and L4_R (SEQ ID NO: 16), PCR amplification was performed under the same conditions, thereby obtaining human IgG1 linker fragments. The subsequent procedure was the same as described above for the construction of fusion proteins containing Fc at the C-terminus.

Example 1-4: Construction of fusion proteins containing Fc at the N-terminus

Three fusion protein expression vectors were constructed containing an Fc at the N-terminus (Fc 42 (SEQ ID NO: 7), Fc 34 (SEQ ID NO: 8) and Fc 28 (SEQ ID NO: 9)). Fc 28, Fc 34, and Fc 42 mean that Fc is fused at the N-terminus of each of the 28, 34, and 42 kD Lefty A proteins.

Using primer pairs L6_F (SEQ ID NO: 18), L7_F (SEQ ID NO: 19), L8_F (SEQ ID NO: 20) and L9_R (SEQ ID NO: 21), fragments 42, 34 and 28 of human Lefty A were generated. Each of the resulting reaction products was separated and purified by 1.5% agarose gel electrophoresis, and then ligated to pCLS05 vector DNA encoding human IgG1 Fc digested with restriction enzyme Xho I using the In-Fusion® HD Cloning Kit (Clontech, 639650) at 50°C for 15 minutes. The subsequent procedure was the same as described above for the construction of fusion proteins containing Fc at the C-terminus.

Example 1-5: Construction of fusion proteins containing HSA at the C-terminus

The fusion protein containing human IgG1 Fc forms a homodimer when expressed in animal cells. For this reason, human serum albumin (HSA) fusion proteins have been designed to construct monomeric fusion proteins. Three fusion protein expression vectors were constructed containing HSA at the C-terminus (42 HSA (SEQ ID NO: 10), 34 HSA (SEQ ID NO: 11) and 28 HSA (SEQ ID NO: 12)). 28 HSA, 34 HSA, and 42 HSA mean that HSA is fused at the C-terminus of each of the 28, 34, and 42 kD Lefty A proteins.

Using the primer pair L1_F (SEQ ID NO: 13) and L9_R (SEQ ID NO: 21), Lefty A fragments 42, 34 and 28 were generated in the same manner as in Example 1. Each of the fragments was digested with restriction enzymes Hind III and Xho I and ligated with pCLS05 vector ligated with Hind III and Xho I at 25°C for 60 minutes. The ligation products were transformed into E. coli DH5α. The transformed cells were cultured overnight in LB medium containing 100 μg/ml ampicillin, and plasmids were extracted from the resulting colonies and then sequenced, thereby confirming the first step of cloning.

In a second cloning step, using the human serum albumin gene synthesized by Bioneer as a template and a pair of primers L10_F (SEQ ID NO: 22) and L11_R (SEQ ID NO: 23), fragments containing human serum albumin were obtained, while the same PCR conditions as used in Example 1. The resulting PCR products were separated and purified by electrophoresis in 1.5% agarose gel, and then ligated with DNA (coding 42, 34 and 28 fragments of human Lefty A obtained in the first stage of cloning), cleaved restriction enzyme Xho I using the In-Fusion® HD Cloning Kit (Clontech, 639650) at 50°C for 15 minutes. The subsequent procedure was the same as described above for the construction of fusion proteins containing Fc at the C-terminus.

A schematic diagram of the expression vectors constructed in Examples 1-1 - Examples 1-5 is shown in FIG. 1, their amino acid sequences are shown in Table 1 below, and the primers used in constructing the fusion proteins are shown in Table 2 below.

Example 1-6: Transient Expression, Purification and Analysis of Lefty A Human Fusion Proteins

Human Lefty A and its variant proteins were expressed using the Freestyle™ MAX CHO Expression system. In particular, Freestyle™ CHO-S (Chinese hamster ovary) cells (Invitrogen, USA) were transfected with the expression vectors described above and grown in CHO serum-free medium (Invitrogen, USA) for 5 days. The culture medium was centrifuged, the supernatant was collected, filtered and then used to analyze the level of protein expression and purification of Lefty A in the culture medium.

The Fc fusion protein from the culture was purified by Protein A affinity chromatography using MabSelect Protein A resin (GE Healthcare, USA). The protein A resin packed column was equilibrated with phosphate buffered saline (PBS, pH 7.4) and then the filtered cell culture supernatant was loaded onto the column. After washing with 10 column volumes (CV) using PBS, then the protein was eluted using 5 CV elution buffer (0.1 M sodium citrate) and the eluate was neutralized by adding 200 μl of 1 M Tris-HCl (pH 8.0). An Amicon Ultra-15 centrifugal filter (MWCO: 30,000) (Millipore, cat. no. UFC903096) was used to replace the buffer in the eluted recombinant protein fraction with PBS (pH 7.4). Placed the pooled sample of the purified protein fraction, centrifuged at 4000 rpm and 4°C for 10 minutes, diluted 10 times, and then centrifuged three times, thus the buffer was changed 1000 times or more. The purified recombinant protein was filtered through a 25 mm PES syringe filter (0.22 µm; Nalgene, cat. no. NAL-194-2520) on a clean bench, minimizing sample loss, and then sealed and stored at 4°C for no exposing to the environment.

The HSA fusion protein was purified using a CaptureSelectTM HSA affinity matrix (ThermoFisher Scientific, USA) or HiTrap Blue HP resin, which specifically binds to HSA. The filtered culture supernatant was passed through a CaptureSelect affinity column packed with PBS, washed with 20 mM Tris-Cl containing 1 M NaCl, and then eluted with 20 mM Tris-Cl containing 1 M arginine and 1 M NaCl. Alternatively, the prepared culture supernatant was passed through a HiTrap Blue HP column packed with 20 mM sodium phosphate (pH 7.0) as binding buffer so that only the desired protein was bound to the resin, and then the protein was eluted using 20 mM sodium phosphate (pH 7.0). 7.0) using 2 M NaCl. After purification was completed, the protein concentration in each fraction was measured at a wavelength of 280 nm using a NANODROP 2000 spectrophotometer (Thermo Scientific, Cat. No. ND-2000). To determine if each fraction would contain the desired protein, a 1200 series HPLC (Agilent Technologies) was used with an SW×1 Guard column (TOSOH, cat. no. 08543) and a TSKgel G3000SW×1 (TOSOH, cat. HPLC by size.

Each of the purified fusion proteins was analyzed by SDS-PAGE and size exclusion chromatography (SEC). SDS-PAGE was performed on Tris/glycine 4-12% acrylamide gel (Invitrogen, USA). The assay gel was stained with Coomassie blue and visualized by digital scanning. Each of the purified proteins was analyzed by size exclusion chromatography (SEC) using a TSK-GEL G300 SWXL column (7.8×300 mm, Tosohaas, USA) equilibrated with phosphate buffered saline containing 0.02% NaN ₃ at a flow rate of 0.5 ml/min, thus determining the level of expression and the purity of the protein. The results are shown in Table 3 below.

Fc fusion protein 34 or 28 was not expressed regardless of the Fc fusion site. In the case of the "42" fragments, the expression efficiency of the C-terminal fusion protein ("42 Fc") was significantly increased compared to the expression efficiency of the N-terminal fusion protein ("Fc 42"), and in particular in the case of a fusion with Fc through the linker ("42 LFc") protein expression efficiency increased significantly. Furthermore, in the case of HSA fusion proteins, only 42 HSAs were expressed, and neither 34 HSAs nor 28 HSAs were expressed. This was also confirmed by culture western blotting (FIG. 2).

Based on these expression data and the in vivo efficacy data described in Example 6, 42 Fc or 42 LFc was used later as a template in the construction of the variants.

Example 2: Construction of Human Lefty A Fusion Protein Variants with Improved Performance and Stability

Based on the expression vector described in Example 1, Lefty A fusion protein variants were constructed with improved protein stability and expression in animal cells compared to 42 LFc.

Example 2-1: Construction of Human Lefty A Fusion Protein Variant Expression Vectors

The propeptide-deleted fusion proteins constructed in Example 1 were largely not expressed. Even the 42 LFc protein was poorly expressed in host cells, and the purified protein was of low purity and lower yield. As shown in FIG. 3, after affinity purification of 42 LFc proteins, additional smaller bands appeared on SDS-PAGE gel, which may be due to cleavage at processing sites or non-specific cleavage due to protein instability (FIG. 3). In addition, potential cleavage sites cleaved by various enzymes and chemicals in the human Lefty A sequence were predicted using ExPASy PeptideCutter DB (https://web.expasy.org/peptide_cutter/), and as a result, it was predicted that leucine residues at positions 311 and 359 are cleaved by the enzyme thrombin. Thus, the propeptide domain, processing sites, and positions of L311, P313, R314, L359, P361, and R362 were mutated to increase the expression level, stability, and purity of human Lefty A fusion protein variants. Using the 42 LFc gene as a template and the primer pairs shown in Table 4 below, the corresponding fragments were obtained by PCR under the same conditions as described in Example 1, and then subjected to a PCR assembly reaction. Each of the resulting reaction products was separated and purified by 1.5% agarose gel electrophoresis and then ligated to pCLS05 vector digested with restriction enzymes Hind III and Xho I using the In-Fusion® HD Cloning Kit (Clontech, 639650) at 50 °C for 15 minutes. The subsequent procedure was the same as described above for the construction of fusion proteins containing Fc at the C-terminus.

The amino acid sequences of the variant in which amino acid residues were changed in the propeptide domain (L22-S73) in the 42 LFc sequence are shown in Table 5 below.

LFB 42 LFc is a variant in which the amino acid residues E24G, S38K, V42T, K50E, A55T, V63A and R66Q have been changed in the 42 LFc sequence.

The amino acid sequences of the variant in which the amino acid residues were changed at the processing sites (R74-R77 and R132-R135) in the 42 LFc sequence are shown in Table 6 below.

42 LFc V1 is a variant in which the G132R amino acid residue has been changed in the 42 LFc sequence; 42 LFc V2 is a variant in which the G132R and R135G amino acid residues are changed in the 42 LFc sequence; and 42 LFc V3 is a variant in which the G132R and G134E amino acid residues are changed in the 42 LFc sequence. 42 LFc V4 is a variant in which the amino acid residue R135G was changed in the 42 LFc sequence; 42 LFc V5 is a variant in which the G74R and G77A amino acid residues are changed in the 42 LFc sequence; 42 LFc V6 is a variant in which the amino acid residues G74R, G77A, G132R and R135A have been changed in the 42 LFc sequence; 42 LFc V7 is a variant in which the amino acid residues G74R, G77A, G132R and R135V have been changed in the 42 LFc sequence; 42 LFc V8 is a variant in which the G74R and G77V amino acid residues are changed in the 42 LFc sequence; 42 LFc V9 is a variant in which the amino acid residues G74R, G77V, G132R and R135A have been changed in the 42 LFc sequence; 42 LFc V10 is a variant in which the amino acid residues G74R, G77V, G132R and R135V have been changed in the 42 LFc sequence; 42 LFc V11 is a variant in which the amino acid residues G74R, G75H, K76G, G132R and R135G have been changed in the 42 LFc sequence; 42 LFc V12 is a variant in which the amino acid residues G74R, G132R and R135G have been changed in the 42 LFc sequence; and 42 LFc V13 is a variant in which the amino acid residues G74R, G77A, G132R and R135G have been changed in the 42 LFc sequence.

Table 7 below shows the amino acid sequences of variants in which the following amino acid substitutions were made: substitutions of amino acid residues in the propeptide domain (L22-S73) as shown in Table 5 above; amino acid residue substitutions at processing sites (R74-R77 and R132-R135) as shown in Table 6 above; and an additional amino acid residue change at the fragmentation site (S202 or S223).

CX196 is a variant with E24G, S38K, V42T, K50E, A55T, V63A, R66Q, G132R, and R135G amino acid substitutions in the 42 LFc sequence, and CX197 is a variant with E24G, S38K, V42T amino acid substitutions , K50E, A55T, V63A, R66Q, G132R and R135AA in the sequence 42 LFc.

CX201 is a variant in which the amino acid residues V63A, R66Q, G132R and R135A are substituted in the 42 LFc sequence, and CX203 is a variant in which the amino acid residues V63A, R66Q, G132R and G134E are substituted in the 42 LFc sequence.

CX206 is a variant in which the amino acid residues of V63A, R66Q, G132R, R135G and S202T are substituted in the 42 LFc sequence, CX207 is a variant in which the amino acid residues of V63A, R66Q, G132R, R135G and S223G are substituted in the 42 LFc sequence, and CX208 is a variant in which the amino acid residues V63A, R66Q, G132R, R135G, S202T and S223G are changed in the 42 LFc sequence.

Table 8 below shows a variant in which the amino acid residues at the thrombin cleavage site (L311, P313, R314, L359, P361 or R362) were replaced in the CX201 sequence shown in Table 7 above.

(UniProt: A0A0C4DH73; SEQ ID NO: 132).For the thrombin site variant, the antibody-derived sequence was used as the signal sequence

(UniProt: A0A0C4DH73; SEQ ID NO: 132).

Example 2-2: Temporal Expression and Purification

The constructed expression vectors were transfected, and the protein was expressed and purified in the same manner as in Example 1, and then its expression level and purity were analyzed. The results are shown in tables 9 to 12 below.

The 42-LFc fusion protein used as the basis for constructing the variants showed an expression level of about 2.8 μg/ml and showed an average protein purity of about 64.3% as measured by size exclusion HPLC after the first affinity purification. The Lefty A variant, made by replacing LFB in the propeptide domain, showed an approximately 7.5-fold increase in expression and showed an average protein purity of approximately 83% as measured by size exclusion HPLC. The V63A substitution in the human Lefty A propeptide domain increased the expression level by about 2-fold, and the V63A/R66Q double substitution increased the expression by about 2.3-fold (Table 9).

I

I

Mutations in the sequence were introduced at the processing sites, and as a result, protein purity, measured by size exclusion HPLC, was 84.1% in 42 LFc V2, and the level of expression of 42 LFc V2 was similar to the level before the introduction of mutations. 42 LFc V6 showed the highest protein purity of 90.9%, but its expression level decreased to about 60% compared to the level before the introduction of mutations (table 10).

Human Lefty A fusion protein variants (combination) were analyzed and as a result, CX196 generated using the LFB propeptide showed an approximately 1.8-fold increase in expression level and increased protein purity to 94.1%, and CX201 generated using human propeptide showed an approximately 1.9-fold increase in expression level and an increase in protein purity to 91.3% (Table 11 and FIG. 4).

Variants of the human Lefty A fusion protein (thrombin cleavage site) were analyzed and as a result a single P361S mutant showed an approximately 1.5-fold increase in expression level. Double mutants L311D/R362Q and L311E/R362Q and triple mutants L311D/P361D/R362Q and L311E/P361D/R362Q all showed a protein purity of about 95% (corresponding to an increase of about 9%) together with a 1.5-fold increase in expression level ( table 12).

Example 3 Improved Serum Stability

Using the human Lefty A fusion protein variants (thrombin cleavage site) constructed in Example 2, an in vitro serum stability test was performed. Each protein variant was diluted in mouse serum or plasma to a final concentration of 10 μg/ml, incubated at 37° C. for 4 hours, and then analyzed by sandwich ELISA. Mouse serum stability was analyzed by measuring the relative remaining amount of each human Lefty A variant in serum under in vitro conditions, and the relative stability of each variant relative to CX201 is shown in Table 13 below. It can be confirmed that when a putative thrombin site mutation such as L311D, L311E, P361D or R362Q occurred, the serum stability of the variant increased.

Example 4: Example 4: Measuring Binding Affinity for Nodal

Binding affinity between the human Nodal protein and the human Lefty A fusion protein variant was measured using the BIAcore.

In particular, 50 RU of the human Nodal protein (R&D systems, 3218-ND-025/CF) was fixed on a CM5 sensor chip. Human Lefty A fusion protein and variants thereof were diluted to concentrations of 500, 250, 125, 62.5, and 31.25 nM and administered sequentially from lower concentrations. Each dilution was then bound by injection at a flow rate of 30 μl/min for 3 minutes and dissociated using running buffer for 5 minutes. The chip was regenerated using 15 μl of 50 mM NaOH. Association and dissociation rates for each cycle were evaluated using the "divalent analyte" model in the BIAevaluation software version 4.1, and the BIAcore data are summarized in Table 14 below.

Example 5 Prevention of ER Stress-Induced Schwann Cell Apoptosis with Human Lefty A Protein

In this study, in order to identify a substance for the treatment of hereditary peripheral neuropathy, a Schwann cell model was developed using a drug that causes endoplasmic reticulum (ER) stress, and it was used to identify drugs.

First, when mesenchymal stem cells were co-cultured in the endoplasmic reticulum stress cellular model, cell death was effectively suppressed while endoplasmic reticulum stress was reduced. ER stress-induced apoptosis of Schwann cells was prevented by co-cultivation with mesenchymal stem cells. In particular, thapsigargin-induced ER stress was induced in S16 Schwann cells in a transwell chamber, and then umbilical cord-derived mesenchymal stem cells were co-cultured in the upper chamber, and S16 cell death was analyzed. At this time, co-culture of umbilical cord-derived mesenchymal stem cells inhibited S16 Schwann cell death by 30% or more (FIG. 5).

From this result, it can be concluded that paracrine factor secreted by umbilical cord stem cells inhibited Schwann cell death. In addition, cytokine antibody sequence analysis was performed to identify a therapeutic protein secreted by mesenchymal stem cells. A protein was analyzed whose secretion by umbilical cord stem cells during co-cultivation with Schwann cells increased by two or more times. In particular, it was observed that the secretion of the Lefty A protein was effectively increased.

Example 6 Improvement of Nerve Function with Human Lefty A Fusion Protein in Tr-J Mice

To test whether human Lefty A fusion protein would improve nerve function, an electrophysiological study was performed using Trembler-J (Tr-J) mice, an animal model of CMT1 (Meekins et al., J Peripher Nerv Syst 9(3):177-82 (2004)). Tr-J mice are spontaneously mutated mice that have an L16P mutation in the PMP22 gene. Tr-J mice have a peripheral nerve demyelination phenotype and show decreased nerve conduction velocity and compound muscle action potential (CMAP) as observed in patients with CMT1 (Henry et al., J Neuropathol Exp Neurol 2 (6):688-706 (1983); Valentijin et al., Nat Genet 2(4):288-911992 (1992)).

Tr-J mice were intraperitoneally injected with PBS or human Lefty A fusion proteins (1 μg/kg) every two days for a total of 8 times from day 6 postnatally (p6) to day 20 postnatally (p20). On the eve of the study of nerve conduction, the hair on the hind limbs was shaved off and removed. The next day, the mice were anesthetized and an active recording needle electrode was placed in the gastrocnemius muscle and a reference electrode was placed directly below the recording electrode to assess nerve conduction in the sciatic nerve of the mice. The stimulating cathode was placed in the femoral region at a distance of 6 mm from the recording electrode, and the amplitude of the compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) were measured using the Nicolet VikingQuest device (Natus Medical, San Carlos, California).

As shown in FIG. 6 and Table 15 below, a nerve conduction study showed that the 42LFc fusion protein improved nerve function in Tr-J mice.

At a dose of 1 μg/kg human LFc fusion protein Lefty A significantly increased the composite muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) of Tr-J mice compared to PBS or HSA fusion protein. These data suggest that human Lefty A fusion protein can be used to improve nerve function in patients with neuropathy.

Example 7 Stimulation of Schwann Cell Myelination by Lefty A Human Fusion Protein Variant

Treatment of the Lefty A (42 LFc; X-42) fusion protein variant of Schwann cells RT4-D6P2T resulted in increased expression of Krox20, an important transcriptional regulator of Schwann cell myelination, and myelin basic protein (MBP), whose expression is induced during myelination (FIG. 7A ).

On the other hand, Nodal treatment of Schwann cells with RT4-D6P2T resulted in a decrease in Krox20 expression, and Nodal myelination inhibition was restored with the Lefty A fusion protein variant (FIGS. 7B and 7C). These results indicate that the Lefty A fusion variant promotes Schwann cell myelination, which is achieved by inhibiting nodal, which acts as a negative regulator of Schwann cell myelination.

Example 8 Improvement of Nerve and Motor Functions by Intraperitoneal Injection (IP) of Lefty A (X-42) Human Fusion Protein Variant in C22 Mice (p6 Mice)

C22 [lineage: (C57BL/6J×CBA/CA)F1] mice are transgenic mice carrying 7 copies of the human PMP22 gene and have a severe peripheral neuronal demyelination phenotype, and have been extensively studied as an animal model of Charcot-Marie-Tooth disease type 1A (CMT1A) (Robertson et al., J Anat 200(4):377-90 (2002); Norreel et al., Neuroscience 116(3):695-703 (2003)). Human fusion protein variant Lefty A (42 LFc; X-42) was intraperitoneally administered to mice at a dose of 10 μg/kg for a total of 10 times every two days from day 6 after birth (p6) to day 24 after birth (p24 ), and assessed nerve conduction and muscle motor activity.

Example 8-1 Nerve Conduction Test

On the eve of the study of nerve conduction, the hair on the hind limbs was shaved off and removed. The next day, the mice were anesthetized and an active recording needle electrode was placed in the gastrocnemius muscle and a reference electrode was placed directly below the recording electrode to assess nerve conduction in the sciatic nerve of the mice. The stimulating cathode was placed in the femoral region at a distance of 6 mm from the recording electrode and the amplitude of the compound muscle action potential (CMAP) and the motor nerve conduction velocity (MNCV) were measured using the Nicolet VikingQuest device (Natus Medical, San Carlos, CA). C22 mice showed significantly reduced MNCV and CMAP compared to wild-type mice. On the other hand, C22 mice injected with the human Lefty A fusion protein variant showed significantly increased MNCV and CMAP compared to the vehicle treated group (FIG. 8).

Example 8-2: Behavior Analysis

To assess the motor function, a rotating rod test and an analysis of the grip strength of the hind limbs were performed.

Specifically, the rotating rod test was performed by placing a mouse on a 3 cm horizontal rotating rod (2 m/min) and then measuring the holding time. Before the test, mice were trained for 3 days, and the test was performed four times a week. The delay before falling off the rotating rod was recorded with a maximum limit set at 5 minutes. As shown in FIG. 9A, the locomotor ability of C22 mice was much lower than that of wild-type mice. Administration of the Lefty A human fusion protein variant significantly improved the motor performance of C22 mice in the rolling rod test (FIG. 9A).

The grip strength of the hind limbs of C22 mice at the age of 3-4 weeks was assessed using a grip strength meter. The mice were allowed to lean on the corner grid facing away from the measuring instrument with their hind limbs. As soon as the mouse grasped the metal mesh or triangular rod with the fingers of its hind limbs, it was pulled by the tail directly to the measurer at a constant speed. The peak force was recorded by the device in grams (g). C22 mice had reduced hind limb strength compared to wild-type mice, and treatment with the Lefty A human protein variant showed a significant therapeutic effect on grip strength (FIG. 9B). Hind limb grip strength in C22 mice injected with the human Lefty A fusion protein variant increased approximately 3-fold (FIG. 9B).

Example 9 Increased Muscle Mass by Intraperitoneal Injection (IP) of Lefty A (X-42) Human Fusion Protein Variant in C22 Mice (p6 mice)

The change in muscle mass induced by the human Lefty A fusion protein variant was examined using 6-day-old (p6) wild-type or C22 mice. PBS or Lefty A human fusion protein variant (10 μg/kg) was administered to mice intraperitoneally at a dose of 10 μg/kg for a total of 10 times every two days from day 6 (p6) to day 24 (p24), and then measured the area of the gastrocnemius muscle using magnetic resonance imaging. Administration of the human fusion protein variant Lefty A showed a significant increase in muscle mass in model CMT1 mice as well as in wild-type mice (FIG. 10).

Example 10 Gait Improvement by Intraperitoneal Injection (IP) of Lefty A (X-42) Human Fusion Protein Variant in C22 Mice (p6 Mice)

To investigate the effect of the Lefty A fusion protein variant on the gait of C22 mice, 6-day-old mice were injected 10 times (every two days) with PBS or the human Lefty A fusion protein variant (10 μg/kg) ip. After the mice were allowed to cross the restricted path, gait was monitored and hip, knee and ankle joint angles were analyzed, as well as two parameters (stride length and base of support (BOS)) (FIG. 11). The stride length was calculated by tracking the right hind paw and the left hind paw, and the BOS value was determined by calculating the step of the left and right limbs. As a result, an improvement in hindlimb stride length was observed in the group of mice treated with the Lefty A fusion protein variant (right in FIG. 11).

Compared to wild-type mice, C22 mice showed significant differences in hip, knee, and ankle joint angles due to gait abnormalities. However, the change in angle in C22 mice was reduced when the lefty A fusion protein was administered to C22 mice (bottom left of FIG. 11). This result shows that neuromuscular function was improved to some extent, but not at the level of wild-type mice.

Example 11 Improvement of Nerve and Motor Functions by Intraperitoneal Injection (IP) of Lefty A (CX201) Human Fusion Protein Variant in C22 Mice (p6 Mice)

C22 mice were intraperitoneally injected with the Lefty A human fusion protein variant CX201 at 0.2 mg/kg, 10 times in total every two days. The injection was started already on the 6th day after birth, when myelination did not start even under normal conditions. Then, as described in Example 8 above, conducted the study of nerve conduction and behavioral analysis.

C22 mice injected with the Lefty A CX201 human fusion protein variant showed significant increases in motor nerve conduction velocity (MNCV) and compound muscle action potential (CMAP) compared to the vehicle injected group (FIG. 12).

In addition, as shown in FIG. 13, C22 mice injected with CX201 showed statistically significant improvements in hindlimb grip strength and roll bar motor performance compared to vehicle-treated controls.

Example 12 Effect on Gait by Intraperitoneal Injection (IP) of Lefty A (CX201) Human Fusion Protein Variant in C22 Mice (p6 Mice)

To investigate the effect of Lefty A fusion protein variant CX201 on gait in C22 mice, PBS or human Lefty A fusion protein variant (200 μg/kg) was administered intraperitoneally to 6-day-old mice 10 times (once a day every two days), and then gait analysis as described in Example 10.

In particular, heel-to-heel stride length analysis showed that the gait of C22 mice treated with the Lefty A fusion protein variant was significantly improved (FIG. 14).

Example 13: Improvement of Neural and Motor Functions by Subcutaneous Injection of Lefty A Human Fusion Protein Variant in C22 Mice (p21 Mice)

Human fusion protein variant Lefty A CX201 was administered subcutaneously to C22 mice at day 21 postnatally (p21), when myelination is predominant, and as described in Example 8 above, nerve conduction studies and behavioral analysis were performed.

C22 mice treated with CX201 for 4 weeks showed a significant increase in both motor nerve conduction velocity and mixed muscle action potential compared to the vehicle treated group (FIG. 15). In particular, hindlimb grip strength increased in male mice with statistical significance (FIG. 16). These data suggest that administration of the CX201 fusion protein variant in the late myelination stage as well as in the early postnatal stage may improve neural and motor function.

Example 14: Inhibition of Myostatin Signaling by Human Fusion Protein Lefty A Variant

Reporter gene analysis was used to evaluate whether the human Lefty A fusion protein variant could inhibit myostatin signaling. A204 rhabdomyosarcoma cells were transfected with the Smad2/3-reactive luciferase reporter vector pGL4.48 (Promega, USA), and then cells stably transfected with the vector were selected using antibiotic selection. Myostatin was pre-incubated with increasing concentrations of the Lefty A human fusion protein variant for 45 minutes. After adding the medium, the cells were incubated for 6 hours, and then myostatin-induced luciferase activity was determined using the bio-glo luciferase assay reagent (Promega, USA). Myostatin induced strong luciferase expression in the stably introduced vector cell line, and the human fusion protein Lefty A variant dose-dependently inhibited myostatin signaling (FIG. 17).

Example 15 Inhibition of p38 Signaling by Lefty A Human Fusion Protein Variant

BMP7 of the TGF-b family is known to suppress myelin gene expression and slow down peripheral myelination through p38 phosphorylation (Liu X et al., Sci Rep 6:31049 (2016)). Thus, it was investigated whether the lefty human fusion protein variant A can inhibit p38 phosphorylation. In particular, the human Lefty A fusion protein variant was administered to C22 mice as described in Example 7, phosphorylated p38 of the sciatic nerve was analyzed using a Western blot method.

As shown in FIG. 18, p38 phosphorylation was inhibited and MBP protein expression increased in the sciatic nerve of C22 mice injected with the human Lefty A fusion protein variant. These data indicate that the human Lefty A fusion protein variant can promote myelination by blocking signaling of p38, a negative regulator of myelination. Therefore, human Lefty A fusion protein can be used as an agent for the treatment of peripheral neuropathy such as demyelination-induced neurodegenerative disease.

Example 16: Construction of a cell line producing human fusion protein variant Lefty A

в качестве сигнальной последовательности в слитом белке СХ201; человеческий Lefty А, связанный с Fc человеческого IgG1 через линкер

SEQ ID NO: 133 в таблице 16) помещали в коническую пробирку объемом 50 мл и добавляли OptiPRO SFM до конечного объема 1,5 мл с последующим перемешиванием на вортексе. 50 мкл реагента Freestyle МАХ помещали в другую коническую пробирку на 50 мл и добавляли OptiPRO SFM до конечного объема 1,5 мл с последующим перемешиванием на вортексе. Раствор Freestyle МАХ добавляли к раствору ДНК, и затем оставляли на 10 минут при комнатной температуре. Через 10 минут колбу Эрленмейера, содержащую клетки, обрабатывали комплексом реагентов DNA-Freestyle МАХ для трансформации клеток.CHO-S cells (cGMP bank) were inoculated into 30 ml of CD-FortiCHO medium in a 125 ml Erlenmeyer flask at a density of 1×10 ⁶ cells/ml. 50 μg of expression vector inserted with human Lefty A fusion protein variant (CX201s; containing antibody-derived sequence

as a signal sequence in the CX201 fusion protein; human Lefty A linked to human IgG1 Fc via a linker

SEQ ID NO: 133 in Table 16) was placed in a 50 ml conical tube and OptiPRO SFM was added to a final volume of 1.5 ml, followed by vortexing. 50 µl of Freestyle MAX reagent was placed in another 50 ml conical tube and OptiPRO SFM was added to a final volume of 1.5 ml followed by vortexing. The Freestyle MAX solution was added to the DNA solution, and then left for 10 minutes at room temperature. After 10 minutes, the Erlenmeyer flask containing the cells was treated with the DNA-Freestyle MAX Reagent Complex to transform the cells.

The first screen and the second screen were performed sequentially to induce gene amplification. The cell line producing CX201s was selected using ClonePix from the pool showing the highest level of expression among the pools obtained after completion of the first and second screens. Selected clones were cultured for 6 days and then suspended in freezing medium (CD-FortiCHO medium 90% plus DMSO 10%) to a concentration of 1.0×10 ⁷ cells/ml, and 1 ml of suspension in each cryovial, thereby obtaining an RCB (Research Cell Bank).

CX201 is a variant in which the amino acid residues V63A, R66Q, G132R and R135A are substituted in the 42 LFc sequence, and CX203 is a variant in which the amino acid residues V63A, R66Q, G132R and G134E are substituted in the 42 LFc sequence.

Example 17: Improvement of Neural Motor Functions by Subcutaneous Injection of Lefty A Human Fusion Protein Variant in C22 Mice (p35 Mice)

5-week-old (p35) C22 mice undergoing peripheral nerve myelination were injected subcutaneously with the lefty A CX201s fusion protein variant human once or twice a week at 5 mg/kg or once a week at 10 mg/kg. Electrophysiological evaluation of nerve function was performed as described in Example 8. C22 mice injected with CX201s showed significant increases in both nerve conduction velocity (NCV) and compound muscle action potential (CMAP) compared to the vehicle injected group (FIG. 19).

A rotating rod test and grip force analysis were performed to assess motor function. For the rotating rod test, the mouse was placed on the rod rotating at 12 rpm and the delay before falling off the rod was recorded with the maximum limit set at 200 seconds. As shown in FIG. 19, roll bar motor performance in C22 mice injected with CX201s was significantly improved compared to vehicle-treated controls. In addition, to assess the neuromuscular function of mice, the grip strength of all limbs of mice was measured using a grip force meter. When C22 mice were treated with CX201s twice a week at 5 mg/kg, all-limb grip strength was statistically significantly improved (FIG. 20).

Taken together, subcutaneous injection of the human variant Lefty A CX201s fusion protein into 5-week-old C22 mice for four or more weeks improved C22 nerve conduction and motor function. In particular, the most effective was the introduction of CX201s at a dose of 5 mg/kg twice a week.

Example 18: Inhibition of Nodal-Induced Signaling by Lefty A Human Fusion Protein Variant

Nodal, a member of the TGF-β family, activates Smad signaling. Once Nodal binds to activin receptors, Smad2 and Smad3 are phosphorylated, bind to Smad4, move to the nucleus, and then regulate the transcription of various genes. The effect of the human fusion protein variant Lefty A on Nodal-induced Smad signaling was evaluated using the Nodal-responsive mouse embryonic cancer cell line P19.

Nodal was pre-incubated with various concentrations of the Lefty A CX201s human fusion protein variant for 30 minutes. Cells were treated with Nodal alone or Nodal-Lefty A fusion protein variant A for 1 hour and then Nodal-induced Smad3 phosphorylation was assessed using cell lysates by Western blot analysis. Treatment of cells with Nodal protein alone induced strong Smad3 phosphorylation, which was dose-dependently inhibited by the human fusion protein variant Lefty A (FIG. 21).

Industrial Applicability

In accordance with the present invention, a variant of the human Lefty A protein and a fusion protein containing said variant are constructed that have better stability than the natural human Lefty A protein and thus are expressed at high levels and produced in high yield in animal cells. In addition, administration of the human engineered Lefty A protein or fusion protein can restore neural and motor function in animal models of peripheral neuropathy. Accordingly, the use of the human Lefty A variant or fusion protein can effectively prevent or treat various nerve diseases and muscle diseases.

Although the present invention has been described in detail with reference to specific features, it will be apparent to those skilled in the art that this description relates only to the preferred embodiment and does not limit the scope of the present invention. Thus, the essential scope of the present invention will be defined by the appended claims and their equivalents.

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SEQUENCE LIST

<110> CHONG KUN DANG PHARMACEUTICAL CORP.

SAMSUNG LIFE PUBLIC WELFARE FOUNDATION

<120> FUNCTION PROTEIN CONTAINING LEFTY HUMAN PROTEIN VARIANTS A, AND

ITS APPLICATION

<130> PF-B2272

<140> PCT/KR2019/017917

<141> 2019-12-17

<150> KR 10-2018-0166802

<151> 2018-12-20

<160> 178

<170>PatentIn version 3.5

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Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 5

<211> 558

<212> Protein

<213> Artificial sequence

<220>

<223> 34 LFc

<400> 5

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg

20 25 30

Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu

35 40 45

Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu

50 55 60

Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His Gly Arg Leu

65 70 75 80

Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val

85 90 95

Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val

100 105 110

Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val

115 120 125

Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln

130 135 140

Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His

145 150 155 160

Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu

165 170 175

Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln

180 185 190

Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys

195 200 205

Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn

210 215 220

Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr

225 230 235 240

Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly

245 250 255

Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val

260 265 270

Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro

275 280 285

Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val

290 295 300

Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

305 310 315 320

Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr

325 330 335

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

340 345 350

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

355 360 365

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

370 375 380

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

385 390 395 400

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

405 410 415

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

420 425 430

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

435 440 445

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

450 455 460

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

465 470 475 480

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

485 490 495

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

500 505 510

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

515 520 525

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

530 535 540

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

545 550 555

<210> 6

<211> 500

<212> Protein

<213> Artificial sequence

<220>

<223> 28LFc

<400> 6

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr

20 25 30

Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu

35 40 45

Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe

50 55 60

Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg

65 70 75 80

Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro

85 90 95

Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala

100 105 110

Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu

115 120 125

Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr

130 135 140

Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly

145 150 155 160

Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala

165 170 175

Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe

180 185 190

Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala

195 200 205

Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro

210 215 220

Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala

225 230 235 240

Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly

245 250 255

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser

260 265 270

Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

275 280 285

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

290 295 300

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

305 310 315 320

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

325 330 335

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

340 345 350

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

355 360 365

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

370 375 380

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

385 390 395 400

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val

405 410 415

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

420 425 430

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

435 440 445

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

450 455 460

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

465 470 475 480

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

485 490 495

Ser Pro Gly Lys

500

<210> 7

<211> 596

<212> Protein

<213> Artificial sequence

<220>

<223> Fc 42

<400> 7

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

20 25 30

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

35 40 45

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

50 55 60

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

65 70 75 80

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

85 90 95

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

100 105 110

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

115 120 125

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

130 135 140

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

145 150 155 160

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

165 170 175

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

180 185 190

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

195 200 205

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

210 215 220

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

225 230 235 240

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Leu Thr Glu Glu Gln

245 250 255

Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val

260 265 270

Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile Pro Ala His Val Arg

275 280 285

Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His Gly Asp Arg Ser Arg

290 295 300

Gly Lys Arg Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu

305 310 315 320

Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu Gln Arg

325 330 335

Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln

340 345 350

Glu Pro Val Pro Lys Ala Ala Leu His Arg His Gly Arg Leu Ser Pro

355 360 365

Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp

370 375 380

Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val

385 390 395 400

His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe

405 410 415

Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser

420 425 430

Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu

435 440 445

Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln

450 455 460

Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp

465 470 475 480

Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln

485 490 495

Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val

500 505 510

Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln

515 520 525

Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg

530 535 540

Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile

545 550 555 560

Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met

565 570 575

Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg

580 585 590

Arg Leu Gln Pro

595

<210> 8

<211> 540

<212> Protein

<213> Artificial sequence

<220>

<223> Fc 34

<400> 8

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

20 25 30

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

35 40 45

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

50 55 60

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

65 70 75 80

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

85 90 95

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

100 105 110

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

115 120 125

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

130 135 140

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

145 150 155 160

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

165 170 175

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

180 185 190

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

195 200 205

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

210 215 220

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

225 230 235 240

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Phe Ser Gln Ser Phe

245 250 255

Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu

260 265 270

Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val

275 280 285

Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu

290 295 300

His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr

305 310 315 320

Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu

325 330 335

Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe

340 345 350

Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg

355 360 365

Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro

370 375 380

Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala

385 390 395 400

Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu

405 410 415

Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr

420 425 430

Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly

435 440 445

Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala

450 455 460

Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe

465 470 475 480

Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala

485 490 495

Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro

500 505 510

Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala

515 520 525

Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro

530 535 540

<210> 9

<211> 482

<212> Protein

<213> Artificial sequence

<220>

<223> Fc 28

<400> 9

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

20 25 30

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

35 40 45

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

50 55 60

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

65 70 75 80

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

85 90 95

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

100 105 110

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

115 120 125

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

130 135 140

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

145 150 155 160

Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

165 170 175

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

180 185 190

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

195 200 205

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

210 215 220

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

225 230 235 240

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Leu Ser Pro Arg Ser

245 250 255

Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly

260 265 270

Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu

275 280 285

Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln

290 295 300

Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln

305 310 315 320

Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg

325 330 335

Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu

340 345 350

Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp

355 360 365

Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met

370 375 380

Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu

385 390 395 400

Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro

405 410 415

Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys

420 425 430

Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu

435 440 445

Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val

450 455 460

Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu

465 470 475 480

GlnPro

<210> 10

<211> 951

<212> Protein

<213> Artificial sequence

<220>

<223> 42 human serum albumin (HSA)

<400> 10

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Asp Ala

355 360 365

His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn

370 375 380

Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys

385 390 395 400

Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala

405 410 415

Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu

420 425 430

His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu

435 440 445

Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg

450 455 460

Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg

465 470 475 480

Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn

485 490 495

Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His

500 505 510

Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys

515 520 525

Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu

530 535 540

Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala

545 550 555 560

Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala

565 570 575

Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala

580 585 590

Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His

595 600 605

Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala

610 615 620

Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys

625 630 635 640

Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile

645 650 655

Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala

660 665 670

Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala

675 680 685

Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His

690 695 700

Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu

705 710 715 720

Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr

725 730 735

Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn

740 745 750

Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys

755 760 765

Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val

770 775 780

Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly

785 790 795 800

Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu

805 810 815

Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys

820 825 830

Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val

835 840 845

Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val

850 855 860

Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys

865 870 875 880

Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val

885 890 895

Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala

900 905 910

Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp

915 920 925

Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala

930 935 940

Ser Gln Ala Ala Leu Gly Leu

945 950

<210> 11

<211> 895

<212> Protein

<213> Artificial sequence

<220>

<223> 34 HSA

<400> 11

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg

20 25 30

Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu

35 40 45

Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu

50 55 60

Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His Gly Arg Leu

65 70 75 80

Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val

85 90 95

Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val

100 105 110

Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val

115 120 125

Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln

130 135 140

Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His

145 150 155 160

Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu

165 170 175

Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln

180 185 190

Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys

195 200 205

Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn

210 215 220

Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr

225 230 235 240

Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly

245 250 255

Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val

260 265 270

Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro

275 280 285

Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val

290 295 300

Pro Arg Arg Leu Gln Pro Asp Ala His Lys Ser Glu Val Ala His Arg

305 310 315 320

Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala

325 330 335

Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu

340 345 350

Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser

355 360 365

Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu

370 375 380

Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys

385 390 395 400

Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys

405 410 415

Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val

420 425 430

Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr

435 440 445

Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu

450 455 460

Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln

465 470 475 480

Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg

485 490 495

Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser

500 505 510

Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg

515 520 525

Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu

530 535 540

Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu

545 550 555 560

Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu

565 570 575

Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro

580 585 590

Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met

595 600 605

Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp

610 615 620

Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe

625 630 635 640

Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu

645 650 655

Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala

660 665 670

Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys

675 680 685

Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu

690 695 700

Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg

705 710 715 720

Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val

725 730 735

Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu

740 745 750

Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn

755 760 765

Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr

770 775 780

Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala

785 790 795 800

Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr

805 810 815

Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln

820 825 830

Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys

835 840 845

Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe

850 855 860

Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu

865 870 875 880

Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu

885 890 895

<210> 12

<211> 837

<212> Protein

<213> Artificial sequence

<220>

<223> 28 HSA

<400> 12

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr

20 25 30

Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu

35 40 45

Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe

50 55 60

Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg

65 70 75 80

Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro

85 90 95

Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala

100 105 110

Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu

115 120 125

Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr

130 135 140

Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly

145 150 155 160

Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala

165 170 175

Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe

180 185 190

Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala

195 200 205

Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro

210 215 220

Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala

225 230 235 240

Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Asp Ala His Lys

245 250 255

Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys

260 265 270

Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe

275 280 285

Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr

290 295 300

Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr

305 310 315 320

Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr

325 330 335

Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu

340 345 350

Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val

355 360 365

Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu

370 375 380

Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr

385 390 395 400

Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala

405 410 415

Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro

420 425 430

Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln

435 440 445

Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys

450 455 460

Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe

465 470 475 480

Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu

485 490 495

Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu

500 505 510

Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys

515 520 525

Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu

530 535 540

Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp

545 550 555 560

Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp

565 570 575

Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp

580 585 590

Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr

595 600 605

Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys

610 615 620

Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile

625 630 635 640

Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln

645 650 655

Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr

660 665 670

Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys

675 680 685

Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr

690 695 700

Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro

705 710 715 720

Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg

725 730 735

Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys

740 745 750

Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu

755 760 765

Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu

770 775 780

Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met

785 790 795 800

Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys

805 810 815

Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln

820 825 830

Ala Ala Leu Gly Leu

835

<210> 13

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L1_F

<400> 13

aattaagctt gccaccatgt ggcctctgtg gctctg 36

<210> 14

<211> 24

<212> DNA

<213> Artificial sequence

<220>

<223> L2_R

<400> 14

aggttgcaat cgtcttggga caag 24

<210> 15

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> L3_F

<400> 15

cttgtcccaa gacgattgca acctgagccc aaatcttgtg acaaa 45

<210> 16

<211> 31

<212> DNA

<213> Artificial sequence

<220>

<223> L4_R

<400> 16

aattctcgag tcatttaccc ggagacaggg a 31

<210> 17

<211> 87

<212> DNA

<213> Artificial sequence

<220>

<223> L5_F

<400> 17

gtcccaagac gattgcaacc tagcggcggt ggcggttctg gcggtggtgg aagtggcggt 60

ggcgggtctg agcccaaatc ttgtgac 87

<210> 18

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L6_F

<400> 18

ctctccctgt ctccgggtaa actcaccgaa gagcagttgt tg 42

<210> 19

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L7_F

<400> 19

ctctccctgt ctccgggtaa attcagccaa tcattccgtg ag 42

<210> 20

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L8_F

<400> 20

ctctccctgt ctccgggtaa actctccccc cgaagcgccc ag 42

<210> 21

<211> 43

<212> DNA

<213> Artificial sequence

<220>

<223> L9_R

<400> 21

gaaggcacag ctcgagtcaa ggttgcaatc gtcttgggac aag 43

<210> 22

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> L10_F

<400> 22

gtcccaagac gattgcaacc tgacgctcac aagtctgaag ttgct 45

<210> 23

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> L11_R

<400> 23

agatccacgc ggaaccagct cgagtcacag ccccaaagcg gcctgtga 48

<210> 24

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> L12_F

<400> 24

actctagagg atcgaaccct t 21

<210> 25

<211> 54

<212> DNA

<213> Artificial sequence

<220>

<223> L12_R

<400> 25

gctggcaact agaaggcaca gctcgagtca tttacccgga gacagggaga ggct 54

<210> 26

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L13_F

<400> 26

ggggccgctc tcacagrgga gcagktgctc gggtcattgt tg 42

<210> 27

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L13_R

<400> 27

caacaatgac ccgagcamct gctccyctgt gagagcggcc cc 42

<210> 28

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L14_F

<400> 28

ctcgggtcat tgttgaggca gcttcagctt tcc 33

<210> 29

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L14_R

<400> 29

ggaaagctga agctgcctca acaatgaccc gag 33

<210> 30

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L15_F

<400> 30

cttcagcttt ccgaagtgcc cgtcctggac aag 33

<210> 31

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L15_R

<400> 31

cttgtccagg acggggcactt cggaaagctg aag 33

<210> 32

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L16_F

<400> 32

ccacccgtcc tggacarggc cgatrtggag gggctcgtta tc 42

<210> 33

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L16_R

<400> 33

gataacgagc ccctccayat cggccytgtc caggacgggt gg 42

<210> 34

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L17_F

<400> 34

aaggccgatg tcgagaagct cgttatccca tcc 33

<210> 35

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L17_R

<400> 35

ggatgggata acgagcttct cgacatcggc ctt 33

<210> 36

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L18_F

<400> 36

gggctcgtta tcccagccca tgtccgggct cag 33

<210> 37

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L18_R

<400> 37

ctgagcccgg acatggggctg ggataacgag ccc 33

<210> 38

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L19_F

<400> 38

cgggctcagt acgttgtgtt gctgcaacat tca 33

<210> 39

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L19_R

<400> 39

tgaatgttgc agcaacacaa cgtactgagc ccg 33

<210> 40

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L20_F

<400> 40

tacgttgcct tgctgagacg gtcacacgct agtaga 36

<210> 41

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L20_R

<400> 41

tctactagcg tgtgaccgtc tcagcaaggc aacgta 36

<210> 42

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L21_F

<400> 42

ctgcaacatt cacacgsakm cagaagtgga ggcaag 36

<210> 43

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L21_R

<400> 43

cttgcctcca cttctgkmts cgtgtgaatg ttgcag 36

<210> 44

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L22_F

<400> 44

tacgttgcct tgctgcrgcr ctcacacgct agtaga 36

<210> 45

<211> 36

<212> DNA

<213> Artificial sequence

<220>

<223> L22_R

<400> 45

tctactagcg tgtgagygcy gcagcaaggc aacgta 36

<210> 46

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L23_F

<400> 46

ggggccgccc tcaccggcga gcagttgttg ggc 33

<210> 47

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L23_R

<400> 47

gcccaacaac tgctcgccgg tgagggcggc ccc 33

<210> 48

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L24_F

<400> 48

cgcgcccaat atgtggycct gctccrgcga tctcacggag at 42

<210> 49

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L24_R

<400> 49

atctccgtga gatcgcygga gcaggrccac atattgggcg cg 42

<210> 50

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> L25_F

<400> 50

cgcgcccaat atgtggccct gctccrgcac tctcacggag atagg 45

<210> 51

<211> 45

<212> DNA

<213> Artificial sequence

<220>

<223> L25_R

<400> 51

cctatctccg tgagagtgcy ggagcaggggc cacatattgg gcgcg 45

<210> 52

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> L26_F

<400> 52

aaggccgatg tcgagaagct cgttatccca gcccatgtcc gggctcag 48

<210> 53

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> L26_R

<400> 53

ctgagcccgg acatggggctg ggataacgag cttctcgaca tcggcctt 48

<210> 54

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L27_F

<400> 54

aaggctgccc tgcaccggca tggtcgtctc tccccccgaa gc 42

<210> 55

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L27_R

<400> 55

gcttcggggg gagagacgac catgccggtg cagggcagcc tt 42

<210> 56

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L28_F

<400> 56

ctgcacggcc atggtggcct ctccccccga agc 33

<210> 57

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L28_R

<400> 57

gcttcggggg gagaggccac catggccgtg cag 33

<210> 58

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L29_F

<400> 58

aggagcaggg gcaaggyctt cagccaatca ttc 33

<210> 59

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L29_R

<400> 59

gaatgattgg ctgaagrcct tgcccctgct cct 33

<210> 60

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L30_F

<400> 60

ctgcaccggc atggtgycct ctccccccga agc 33

<210> 61

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L30_R

<400> 61

gcttcggggg gagaggrcac catgccggtg cag 33

<210> 62

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L31_F

<400> 62

ctgcaccggc atggtggcct ctccccccga agc 33

<210> 63

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L31_R

<400> 63

gcttcggggg gagaggccac catgccggtg cag 33

<210> 64

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L32_F

<220>

<221> other_characteristic

<222> (16)..(17)

<223> n is a, c, g, or t

<400> 64

ctccttctgc aagtgnnkgt ccagcgcgaa cac 33

<210> 65

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L32_R

<220>

<221> other_characteristic

<222> (17)..(18)

<223> n is a, c, g, or t

<400> 65

gtgttcgcgc tggacmnnca cttgcagaag gag 33

<210> 66

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L33_F

<220>

<221> other_characteristic

<222> (16)..(17)

<223> n is a, c, g, or t

<400> 66

ctggtgcgat tcgctnnkca gggtgcacca gcc 33

<210> 67

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> L33_R

<220>

<221> other_characteristic

<222> (17)..(18)

<223> n is a, c, g, or t

<400> 67

ggctggtgca ccctgmnnag cgaatcgcac cag 33

<210> 68

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L34_F

<400> 68

ttcaactggc cctttgasgg acctcggcaa tgtattgcca gc 42

<210> 69

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L34_R

<400> 69

gctggcaata cattgccgag gtccstcaaa gggccagttg aa 42

<210> 70

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L35_F

<400> 70

ttcaactggc cctttctcgg agascggcaa tgtattgcca gc 42

<210> 71

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L35_R

<400> 71

gctggcaata cattgccgst ctccgagaaa gggccagttg aa 42

<210> 72

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L36_F

<400> 72

ttcaactggc ccttctctcgg atcccggcaa tgtattgcca gc 42

<210> 73

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L36_R

<400> 73

gctggcaata cattgccggg atccgagaaa gggccagttg aa 42

<210> 74

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L37_F

<400> 74

ttcaactggc cctttctcgg acctmagcaa tgtattgcca gc 42

<210> 75

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L37_R

<400> 75

gctggcaata cattgctkag gtccgagaaa gggccagttg aa 42

<210> 76

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L38_F

<400> 76

gcctctgacg gggctgasgt cccaagacga ttgcaacctt ct 42

<210> 77

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L38_R

<400> 77

agaaggttgc aatcgtcttg ggacstcagc cccgtcagag gc 42

<210> 78

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L39_F

<400> 78

gcctctgacg gggctcttgt cgasagacga ttgcaacctt ct 42

<210> 79

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L39_R

<400> 79

agaaggttgc aatcgtctst cgacaagagc cccgtcagag gc 42

<210> 80

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L40_F

<400> 80

gcctctgacg gggctcttgt ctccagacga ttgcaacctt ct 42

<210> 81

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L40_R

<400> 81

agaaggttgc aatcgtctgg agacaagagc cccgtcagag gc 42

<210> 82

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L41_F

<400> 82

gcctctgacg gggctcttgt cccamagcga ttgcaacctt ct 42

<210> 83

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L41_R

<400> 83

agaaggttgc aatcgctktg ggacaagagc cccgtcagag gc 42

<210> 84

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L42_F

<400> 84

gcctctgacg gggctcttgt cgaccagcga ttgcaacctt ct 42

<210> 85

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> L42_R

<400> 85

agaaggttgc aatcgctggt cgacaagagc cccgtcagag gc 42

<210> 86

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A)

<400> 86

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 87

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(R66Q)

<400> 87

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 88

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R66Q)

<400> 88

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 89

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R67H)

<400> 89

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Arg His Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 90

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R66Q/R67H)

<400> 90

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln His Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 91

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> LFB 42 LFc

<400> 91

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met

35 40 45

Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 92

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V1

<400> 92

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 93

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V2

<400> 93

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 94

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V3

<400> 94

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 95

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V4

<400> 95

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 96

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V5

<400> 96

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 97

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V6

<400> 97

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 98

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V7

<400> 98

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 99

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V8

<400> 99

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 100

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V9

<400> 100

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 101

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V10

<400> 101

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 102

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V11

<400> 102

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg His Gly Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 103

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V12

<400> 103

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 104

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V13

<400> 104

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 105

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX196

<400> 105

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met

35 40 45

Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 106

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX197

<400> 106

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met

35 40 45

Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 107

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX201

<400> 107

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 108

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX203

<400> 108

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 109

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX206

<400> 109

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Thr Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 110

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX207

<400> 110

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 111

<211> 614

<212> Protein

<213> Artificial sequence

<220>

<223>CX208

<400> 111

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu

50 55 60

Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Thr Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly

355 360 365

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro

370 375 380

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

385 390 395 400

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

405 410 415

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

420 425 430

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

435 440 445

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

450 455 460

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

465 470 475 480

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

485 490 495

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

500 505 510

Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys Asn

515 520 525

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

530 535 540

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

545 550 555 560

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

565 570 575

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

580 585 590

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

595 600 605

Ser Leu Ser Pro Gly Lys

610

<210> 112

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L311D)

<400> 112

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 113

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L311E)

<400> 113

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 114

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313D)

<400> 114

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Asp Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 115

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313E)

<400> 115

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Glu Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 116

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313S)

<400> 116

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Ser Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 117

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(R314K)

<400> 117

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Lys Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 118

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(R314Q)

<400> 118

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Gln Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 119

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L359D)

<400> 119

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Asp Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 120

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L359E)

<400> 120

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Glu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 121

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361D)

<400> 121

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 122

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361E)

<400> 122

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Glu Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 123

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361S)

<400> 123

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Ser Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 124

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(R362K)

<400> 124

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Lys Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 125

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(R362Q)

<400> 125

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 126

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311D/R362Q)

<400> 126

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 127

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311E/R362Q)

<400> 127

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 128

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311D/P361D/R362Q)

<400> 128

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Gln Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 129

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311E/P361D/R362Q)

<400> 129

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Gln Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 130

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<223> Linker

<400> 130

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 131

<211> 366

<212> Protein

<213> Artificial sequence

<220>

<223> Human Lefty A

<400> 131

Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala

1 5 10 15

Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu

20 25 30

Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met

35 40 45

Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu

50 55 60

Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gln

65 70 75 80

Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr

85 90 95

His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu

100 105 110

Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala

115 120 125

Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg

130 135 140

Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr

145 150 155 160

Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys

165 170 175

Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg

180 185 190

Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu

195 200 205

Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln

210 215 220

Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu

225 230 235 240

Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro

245 250 255

Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu

260 265 270

Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe

275 280 285

Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu

290 295 300

Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu

305 310 315 320

Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr

325 330 335

Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser

340 345 350

Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro

355 360 365

<210> 132

<211> 22

<212> Protein

<213> Artificial sequence

<220>

<223> signal peptide

<400> 132

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys

20

<210> 133

<211> 615

<212> Protein

<213> Artificial sequence

<220>

<223>CX201s

<400> 133

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu

20 25 30

Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp

35 40 45

Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala

50 55 60

Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser

65 70 75 80

Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser

85 90 95

Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser

100 105 110

Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys

115 120 125

Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala

130 135 140

Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg

145 150 155 160

Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp

165 170 175

Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser

180 185 190

Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His

195 200 205

Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser

210 215 220

Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr

225 230 235 240

Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala

245 250 255

Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp

260 265 270

Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly

275 280 285

Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala

290 295 300

Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser

305 310 315 320

Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg

325 330 335

Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys

340 345 350

Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu

370 375 380

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

385 390 395 400

Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

405 410 415

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

420 425 430

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

435 440 445

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

450 455 460

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

465 470 475 480

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

485 490 495

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

500 505 510

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys

515 520 525

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

530 535 540

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

545 550 555 560

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

565 570 575

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

580 585 590

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

595 600 605

Leu Ser Leu Ser Pro Gly Lys

610 615

<210> 134

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A)

<400> 134

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 135

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(R66Q)

<400> 135

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 136

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R66Q)

<400> 136

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 137

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R67H)

<400> 137

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Arg His Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 138

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc(V63A/R66Q/R67H)

<400> 138

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln His Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 139

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> LFB 42 LFc

<400> 139

Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile

20 25 30

Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 140

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V1

<400> 140

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 141

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V2

<400> 141

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 142

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V3

<400> 142

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 143

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V4

<400> 143

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 144

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V5

<400> 144

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 145

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V6

<400> 145

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 146

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V7

<400> 146

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 147

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V8

<400> 147

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His

100 105 110

Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 148

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V9

<400> 148

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 149

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V10

<400> 149

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 150

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V11

<400> 150

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg His Gly Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 151

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V12

<400> 151

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 152

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> 42 LFc V13

<400> 152

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His

35 40 45

Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 153

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX196

<400> 153

Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile

20 25 30

Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 154

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX197

<400> 154

Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile

20 25 30

Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 155

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201

<400> 155

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 156

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX203

<400> 156

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 157

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX206

<400> 157

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Thr Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 158

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX207

<400> 158

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 159

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX208

<400> 159

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Thr Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 160

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L311D)

<400> 160

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 161

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L311E)

<400> 161

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 162

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313D)

<400> 162

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Asp Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 163

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313E)

<400> 163

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Glu Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 164

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P313S)

<400> 164

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Ser Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 165

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(R314K)

<400> 165

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Lys Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 166

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(R314Q)

<400> 166

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Gln Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 167

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L359D)

<400> 167

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Asp Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 168

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(L359E)

<400> 168

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Glu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 169

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361D)

<400> 169

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Asp Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 170

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361E)

<400> 170

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Glu Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 171

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(P361S)

<400> 171

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Ser Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 172

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(R362K)

<400> 172

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Lys Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 173

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201(R362Q)

<400> 173

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 174

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311D/R362Q)

<400> 174

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 175

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311E/R362Q)

<400> 175

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 176

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311D/P361D/R362Q)

<400> 176

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Asp Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 177

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223> CX201(L311E/P361D/R362Q)

<400> 177

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Asp Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<210> 178

<211> 593

<212> Protein

<213> Artificial sequence

<220>

<223>CX201s

<400> 178

Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu

1 5 10 15

Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile

20 25 30

Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His

35 40 45

Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val

50 55 60

Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe

65 70 75 80

Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val

85 90 95

Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His

100 105 110

Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp

115 120 125

Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser

130 135 140

Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr

145 150 155 160

Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu

165 170 175

Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser

180 185 190

Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly

195 200 205

Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr

210 215 220

Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr

225 230 235 240

Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp

245 250 255

Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys

260 265 270

Val Gly Thr Cys Gln Gln Pro Glu Ala Leu Ala Phe Asn Trp Pro

275 280 285

Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro

290 295 300

Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val

305 310 315 320

Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly

325 330 335

Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly

340 345 350

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys

355 360 365

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

370 375 380

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

385 390 395 400

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

405 410 415

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

420 425 430

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

435 440 445

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

450 455 460

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

465 470 475 480

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

485 490 495

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

500 505 510

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

515 520 525

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

530 535 540

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

545 550 555 560

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

565 570 575

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

580 585 590

Lys

<---

Claims (29)

1. A protein having the activity of the human Lefty A protein, comprising the amino acid sequence L22 to P366 of the human Lefty A protein, having the amino acid sequence of SEQ ID NO: 131, and comprising: (1) a substitution of one or more amino acid residues at processing sites selected from the group consisting of R74G, R77G or R77V, R132G and R135G; And (2) a substitution of one or more amino acid residues in the propeptide domain selected from the group consisting of E24G, S38K, V42T, K50E, A55T, V63A and R66Q. 2. The protein according to claim 1, wherein the substitution of amino acid residues in the propeptide domain from L22 to S73 contains V63A, and additionally contains one or more substitutions of amino acid residues selected from the group consisting of: E24G, S38K, V42T, K50E, A55T and R66Q. 3. A protein according to claim 1, containing the amino acid sequence RGKR, GGKG, RGKA, RGKV or RHGG at positions R74 to R77, and the amino acid sequence RHGR, GHGR, RHGG, RHER, GHGG, RHGA or RHGV at positions R132 to R135. 4. A protein having the activity of the human Lefty A protein, comprising the amino acid sequence L22 to P366 of the human Lefty A protein, having the amino acid sequence of SEQ ID NO: 131, and comprising: (1) a substitution of one or more amino acid residues at processing sites selected from the group consisting of R74G, R77G or R77V, R132G and R135G; (2) a substitution of one or more amino acid residues in the propeptide domain selected from the group consisting of E24G, S38K, V42T, K50E, A55T, V63A, and R66Q; And (3) replacing one or more amino acid residues at the thrombin cleavage site of L311, P313, R314, L359, P361, or R362. 5. The protein according to claim 4, wherein the amino acid residues at one or more positions selected from the group consisting of thrombin cleavage sites L311, P313, R314, L359, P361 and R362 are replaced by amino acid residues selected from the group consisting of aspartic acid (D), glutamic acid (E), serine (S), lysine (K), and glutamine (Q). 6. A protein having the activity of the human Lefty A protein, containing the amino acid sequence L22 to P366 of the human Lefty A protein, having the amino acid sequence of SEQ ID NO: 131, and containing: (1) a substitution of one or more amino acid residues at processing sites selected from the group consisting of R74G, R77G or R77V, R132G and R135G; (2) a substitution of one or more amino acid residues in the propeptide selected from the group consisting of E24G, S38K, V42T, K50E, A55T, V63A and R66Q; And (3) replacing one or more amino acid residues at the fragmentation site S202 or S223 with amino acid residues other than serine (S) and cysteine (C). 7. A protein having the activity of the human Lefty A protein, comprising the amino acid sequence L22 to P366 of the human Lefty A protein, having the amino acid sequence of SEQ ID NO: 131, and containing: (1) a substitution of one or more amino acid residues at processing sites selected from the group consisting of R74G, R77G or R77V, R132G and R135G; (2) a substitution of one or more amino acid residues in the propeptide selected from the group consisting of E24G, S38K, V42T, K50E, A55T, V63A and R66Q; And (3) signal peptide at the N-terminus. 8. Fusion protein for the treatment of neuropathy, containing a protein according to any one of paragraphs. 1-7 fused to Fc or albumin, wherein Fc or albumin is fused to the C-terminus of said protein and said protein and Fc or albumin are fused together via a linker. 9. Fusion protein for the treatment of muscle disease, containing a protein according to any one of paragraphs. 1-7 fused to Fc or albumin, wherein Fc or albumin is fused to the C-terminus of said protein and said protein and Fc or albumin are fused together via a linker. 10. A fusion protein according to claim 8 or 9, wherein said fusion protein has any amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOs: 134-178. 11. A nucleic acid molecule encoding a fusion protein according to any one of paragraphs. 8-10. 12. An expression vector containing the nucleic acid molecule according to claim 11. 13. Recombinant Chinese hamster ovary (CHO) cell for the production of a fusion protein according to any one of paragraphs. 8-10, into which the expression vector of claim 12 has been introduced. 14. Composition for the prevention or treatment of a neuromuscular disease, which includes either a protein according to any one of paragraphs. 1-7, or a fusion protein according to any one of paragraphs. 8-10 in an effective amount and a pharmaceutically acceptable carrier. 15. A composition for preventing or treating a neuromuscular disease according to claim 14, wherein the neuromuscular disease is a disease associated with Nodal or myostatin signaling pathways. 16. A composition for the prevention or treatment of a neuromuscular disease according to claim 15, wherein the disease associated with Nodal or myostatin signaling pathways is a myopathy, peripheral neuropathy, or stiff spine syndrome. 17. A composition for preventing or treating a neuromuscular disease according to claim 16, wherein the myopathy is selected from the group consisting of: sarcopenia, muscular dystrophy, myasthenia gravis, amyotrophic lateral sclerosis (or Lou Gehrig's disease), primary lateral sclerosis, progressive muscular atrophy , Kennedy's disease (or spinobulbar muscular atrophy), spinal muscular atrophy and distal myopathy. 18. A composition for preventing or treating a neuromuscular disease according to claim 17, wherein the peripheral neuropathy is selected from the group consisting of: Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, carpal tunnel syndrome, diabetic peripheral neuropathy, and Guillain-Barré syndrome .

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