Truncated polycystic protein 1 polypeptide and application thereof

Abstract

The present invention comprises: a polynucleotide that contains a sequence encoding truncated polycystic protein 1 (PC1) having a cyst formation inhibiting effect, the truncated PC1 containing a C-terminal tail (CTT) region of PC1 or a part thereof; a truncated PC1 polypeptide encoded by the polynucleotide; a vector containing the polynucleotide; a pharmaceutical composition containing the polynucleotide, polypeptide or carrier for treating PKD1-related diseases, and the like.

Description

Technical Field

[0001] The present invention relates to a truncated polycystin 1 polypeptide and its use, in particular to the treatment of PKD1-related diseases. Background Art

[0002] Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease characterized by the progressive growth and enlargement of multiple cysts in both kidneys and damage to various organs other than the kidneys. ADPKD is a hereditary disease with PKD1 and PKD2 as the pathogenic genes, and 85% of patients are caused by abnormalities in the PKD1 gene. The PKD1 gene encodes polycystin 1 (PC1), an 11-transmembrane protein, and together with polycystin 2 (PC2), a 6-transmembrane protein encoded by the PKD2 gene, participate in Ca 2+ Regulation of influx into cells. It is thought that loss of function of PC1 or PC2 due to mutations in the PKD1 or PKD2 gene leads to cyst formation. Summary of the invention

[0003] Problem that the invention aims to solve

[0004] Gene therapy may be one of the options for the treatment of genetic diseases such as ADPKD, but the PKD1 gene is very large, about 13 kb, and it is difficult to introduce the gene in its original state. In addition, it is not clear which regions of PC1 are necessary for the functional restoration of PC1 and where it should be present in the cell. The object of the present invention is to provide a truncated PC1 that can be used for the functional restoration of PC1 and / or a method for using it.

[0005] Methods used to solve problems

[0006] In one embodiment, the present invention provides a polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1) having a cyst formation inhibitory effect, wherein the truncated PC1 contains a C-terminal tail (CTT) region of PC1 or a portion thereof.

[0007] In one embodiment, the present invention provides a polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1), wherein the truncated PC1 is a membrane-localized polypeptide comprising a C-terminal tail (CTT) region of PC1 or a portion thereof.

[0008] In one embodiment, the present invention provides a truncated PC1 polypeptide encoded by the above polynucleotide.

[0009] In one embodiment, the present invention provides a vector comprising the above-mentioned polynucleotide.

[0010] In one embodiment, the present invention provides a pharmaceutical composition for treating a PKD1-related disease, comprising the above-mentioned polynucleotide or vector.

[0011] Effects of the Invention

[0012] According to the present invention, a truncated PC1 that can be used to restore the function of PC1 can be provided, thereby enabling treatment of PKD1-related diseases, particularly gene therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The structures of PC1, truncated PC1 polypeptide (CTF), and PC1 (Arg1672fs97X) are shown.

[0014] Figure 2 The structures of various truncated PC1 polypeptides are shown.

[0015] Figure 3 The results of evaluating the inhibitory effects of PC1, PC1(Arg1672fs97X) and truncated polypeptides (CTF, CTT) on cyst formation are shown. pEB represents the control. The vertical axis represents the total cyst area (μm 2 ).

[0016] Figure 4 The results of evaluating the inhibitory effect of various truncated PC1 polypeptides on cyst formation are shown. pEB represents the control. The vertical axis represents the total cyst area (μm 2 ).

[0017] Figure 5 The structures of truncated PC1 polypeptides CD16.7-CTT and FAS-CTT are shown.

[0018] Figure 6 The results of evaluating the inhibitory effects of CD16.7-CTT and FAS-CTT on cyst formation are shown. pEB represents the control. The vertical axis represents the total cyst area (μm 2 ).

[0019] Figure 7 Partial regions of the CTT region contained in various truncated PC1 polypeptides are shown. The numbers in the figure represent the amino acid numbers in SEQ ID NO: 1. NLS: nuclear localization signal.

[0020] Figure 8-1 The results of evaluating the inhibitory effect of various truncated PC1 polypeptides containing a partial region of the CTT region (1) are shown. pEB represents the control, and the vertical axis represents the total cyst area (μm 2 )( Figures 8-2 to 8-4 Same).

[0021] Figure 8-2The results of evaluating the cyst formation inhibitory effects of various truncated PC1 polypeptides containing a partial region of the CTT region are shown (2).

[0022] Figure 8-3 The results of evaluating the cyst formation inhibitory effects of various truncated PC1 polypeptides containing a partial region of the CTT region are shown (3).

[0023] Figure 8-4 The results of evaluating the cyst formation inhibitory effects of various truncated PC1 polypeptides containing a partial region of the CTT region are shown (4).

[0024] Figure 9-1 The expression analysis of truncated PC1 polypeptide in MDCK cells by HPLC-MS (identification of peptides in the CTT region) is shown. The vertical axis (abundance) represents the detection intensity of peptides in HPLC-MS ( Figure 9-2 and Figure 10-1~2 Same).

[0025] Figure 9-2 The figure shows the expression analysis of truncated PC1 polypeptide in MDCK cells using HPLC-MS (identification of peptides within the 11th transmembrane region of CTF1).

[0026] Figure 10-1 The figure shows the cell membrane localization analysis of truncated PC1 polypeptide in MDCK cells using HPLC-MS (identification of peptides within the CTT region).

[0027] Figure 10-2 The figure shows the cell membrane localization analysis of truncated PC1 polypeptide in MDCK cells using HPLC-MS (identification of peptides within the 11th transmembrane region of CTF1). DETAILED DESCRIPTION

[0028] Unless otherwise specified, the terms used in this specification have the meanings commonly understood by those skilled in the art in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, etc. The following are definitions of several terms used in this specification, which take precedence over conventional understandings in this specification.

[0029] The PKD1 gene encodes polycystin 1 (PC1), an 11-transmembrane protein with its N-terminus outside the cell and its C-terminus inside the cell. PC1 forms a complex with PC2, a 6-transmembrane protein with both its N-terminus and C-terminus inside the cell, through the coiled-coil domain of the intracellular region, and transmits signals to PC2, which functions as a calcium channel, to induce Ca 2+ Flow into the cells.

[0030] PC1 has GPS (G protein-coupled receptor proteolytic site) as a cleavage site, and is composed of an extracellular N-terminal region on the N-terminal side of GPS and a C-terminal fragment (CTF) region on the C-terminal side of GPS. The CTF region has a stem region (stalk), 11 transmembrane regions, and a C-terminal tail (CTT) region. The stem region is the N-terminal extracellular region of the CTF region, that is, the region from the N-terminal end of the CTF region to the first transmembrane region (TM1). In the present invention, PC1 can be PC1 of a mammal, such as a human or a non-human mammal. In one embodiment, PC1 is human PC1. The representative amino acid sequence of human PC1 is shown in sequence number 1, and the nucleotide sequence encoding it is shown in sequence number 2. Human PC1 and the nucleotide sequence encoding it are each not limited to sequences having sequence numbers 1 and 2. For example, human PC1 can be an amino acid sequence having an amino acid sequence that is different from the amino acid sequence of sequence number 1 in terms of containing natural mutations such as SNPs. In addition, the nucleotide sequence encoding human PC1 may be a nucleotide sequence having a sequence different from that of SEQ ID NO: 2 due to the degeneracy of the genetic code. A person skilled in the art can determine each region of PC1 based on existing reports (Nat Genet, 1995 Jun; 10(2): 151-60; Biochemistry 2003, 42, 13035-13048; Science 361, 992 (2018); Dev Cell 22, 197-210, Jan 17, 2012), or amino acid domain and motif databases, transmembrane region prediction tools, such as Uniprot (https: / / www.uniprot.org / ), NCBI (https: / / www.ncbi.nlm.nih.gov / ), predictprotein (https: / / predictprotein.org / ), etc. In sequence number 1, the extracellular N-terminal region, stem region, 11 transmembrane regions and CTT region can be determined as the amino acid sequences at positions 1 to 3048, 3049 to 3074, 3075 to 4101 and 4102 to 4303, respectively.

[0031] Truncated PC1 refers to a polypeptide lacking a portion of the amino acid sequence of full-length PC1. In addition to containing a partial sequence of PC1, truncated PC1 may also contain sequences that are not derived from PC1. The length of the partial sequence of PC1 in truncated PC1 can be 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200、2100、2000、1900、1800、1700、1600、1500、1400、1300、1200、1100、1000、900、800、700、600、500、400、300、290、280、270、260、250、240、230、220、210 , 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60 or less amino acids, and can be 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 2 00, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 amino acids or more. The length of the partial sequence of PC1 in the truncated PC1 may be 140 to 260, 150 to 250, 160 to 240, 170 to 230, 180 to 220 or 190 to 210 amino acids, for example 226, 202 or 190 amino acids. Alternatively, the length of the partial sequence of PC1 in the truncated PC1 may be 40 to 200, 50 to 150 or 50 to 100 amino acids. The partial sequence of PC1 in the truncated PC1 can be a continuous sequence in the full-length PC1, or it can be composed of multiple discontinuous partial sequences. In one embodiment, the truncated PC1 lacks at least a portion of the extracellular N-terminal region of PC1. In one embodiment, the truncated PC1 lacks the entire extracellular N-terminal region of PC1. In one embodiment, the truncated PC1 lacks the entire extracellular N-terminal region and also lacks at least a portion of the stem region and 11 transmembrane regions of PC1. In one embodiment, the truncated PC1 lacks all of the entire extracellular N-terminal region, stem region, and 11 transmembrane regions of PC1.The length of the truncated PC1 can be 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 210 0, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or more amino acids.

[0032] The truncated PC1 of the present invention contains a CTT region or a portion thereof. In this specification, "containing a CTT region or a portion thereof" has the same meaning as containing "at least a portion of a CTT region". The CTT region is the intracellular region of PC1. The length of the CTT region may be less than 230, 220, 210, 200, 190, 180, 170, 160, 150 or 140 amino acids, and may be more than 140, 150, 160, 170, 180, 190 or 200 amino acids. For example, the length of the CTT region may be 140 to 260, 150 to 250, 160 to 240, 170 to 230, 180 to 220, 190 to 210 amino acids, such as 226, 202 or 190 amino acids, etc.

[0033] In SEQ ID NO: 1, the CTT region can be identified as the amino acid sequence at positions 4102 to 4303 (SEQ ID NO: 3). In SEQ ID NO: 2, the sequence encoding the CTT region can be identified as the nucleotide sequence at positions 12304 to 12909 (SEQ ID NO: 4).

[0034] In one embodiment, the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the CTT region contains the sequence of sequence number 3, or a sequence in which 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the CTT region contains the sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the CTT region contains the sequence of sequence number 3, or is composed of the above sequence.

[0035] The sequence of the polynucleotide encoding the CTT region is not particularly limited as long as it encodes the CTT region described in this specification. In one embodiment, the sequence encoding the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the sequence encoding the CTT region contains a sequence encoding sequence number 3, or a sequence in which 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the sequence encoding the CTT region contains a sequence encoding a sequence of sequence number 3, or is composed of the above sequence. In one embodiment, the sequence encoding the CTT region contains a sequence encoding the sequence at positions 3 to 202 of SEQ ID NO: 3, or consists of the above sequence.

[0036] In one embodiment, the sequence encoding the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 4, or is composed of the above sequence. In one embodiment, the sequence encoding the CTT region comprises the sequence of SEQ ID NO: 4, or a sequence in which 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of SEQ ID NO: 4, or consists of the above sequence. In one embodiment, the sequence encoding the CTT region comprises the sequence of SEQ ID NO: 4, or consists of the above sequence. In one embodiment, the sequence encoding the CTT region contains or consists of the sequence at positions 7 to 606 of SEQ ID NO: 4. The sequence encoding the CTT region may have a sequence different from SEQ ID NO: 4 or the sequence at positions 7 to 606 of SEQ ID NO: 4 due to the degeneracy of the genetic code.

[0037] A portion of the CTT region may be any portion of the CTT region. The length of a portion of the CTT region may be 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60 or less than 50 amino acids, and may be 40, 50, 60, 70, 80, 90, 100 amino acids or more. For example, the length of a portion of the CTT region may be 40 to 200, 50 to 150 or 50 to 100 amino acids.

[0038] In one embodiment, a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4303 of SEQ ID NO: 1, or is composed of the above. In one embodiment, a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4303 of SEQ ID NO: 1, or is composed of the above. In one embodiment, a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4303 of SEQ ID NO: 1, or is composed of the above. In one embodiment, a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4303 of SEQ ID NO: 1, or is composed of the above.

[0039] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4204 to 4243 of SEQ ID NO. 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence.

[0040] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4104 to 4203 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence.

[0041] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4154 to 4253 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence.

[0042] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4154 to 4243 of SEQ ID NO. 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence.

[0043] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4193 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0044] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains the sequence of positions 4204 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0045] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4204 to 4253 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains a sequence of positions 4204 to 4253 of SEQ ID NO. 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4204 to 4253 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4204 to 4253 of SEQ ID NO. 1, or is composed of the above sequence.

[0046] In one embodiment, a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains a sequence of positions 4254 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, a portion of the CTT region contains positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0047] The sequence of the polynucleotide encoding a portion of the CTT region is not particularly limited as long as it encodes a portion of the CTT region described in the present specification. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4154 to 4303 of SEQ ID NO: 1, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises a sequence encoding the 4154th to 4303rd positions of SEQ ID NO. 1, or a sequence encoding 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids in the 4154th to 4303rd positions of SEQ ID NO. 1, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises a sequence encoding at least a portion of the sequence encoding the 4154th to 4303rd positions of SEQ ID NO. 1, or consists of the above sequence.

[0048] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4243 of SEQ ID NO. 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4243 of SEQ ID NO. 1, or is composed of the above sequence.

[0049] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4104 to 4203 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4104 to 4203 of SEQ ID NO: 1, or is composed of the above sequence.

[0050] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4154 to 4253 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4154 to 4253 of SEQ ID NO: 1, or is composed of the above sequence.

[0051] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4154 to 4243 of SEQ ID NO. 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence at positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4154 to 4243 of SEQ ID NO. 1, or is composed of the above sequence.

[0052] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4193 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4193 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0053] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0054] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4204 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4253 of SEQ ID NO: 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4204 to 4253 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4204 to 4253 of SEQ ID NO: 1, or is composed of the above sequence.

[0055] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4254 to 4303 of SEQ ID NO: 1, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains a sequence encoding the sequence at positions 4254 to 4303 of SEQ ID NO: 1, or is composed of the above sequence.

[0056] In one embodiment, the sequence encoding a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence at positions 12460 to 12909 of SEQ ID NO: 2, or consists of the above. In one embodiment, the sequence encoding a portion of the CTT region comprises or consists of the sequence of positions 12460 to 12909 of SEQ ID NO: 2, or a sequence in which 1 to 135, 1 to 130, 1 to 125, 1 to 120, 1 to 115, 1 to 110, 1 to 105, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12460 to 12909 of SEQ ID NO: 2. In one embodiment, the sequence encoding a portion of the CTT region contains or consists of at least a portion of the sequence at positions 12460 to 12909 of SEQ ID NO: 2. The sequence encoding a portion of the CTT region may have a sequence different from at least a portion of the sequence at positions 12460 to 12909 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0057] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12610 to 12729 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12610 to 12729 of SEQ ID NO: 2, or a sequence in which 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 nucleotides are modified in the sequence at positions 12610 to 12729 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12610 to 12729 of SEQ ID NO: 2, or is composed of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12610 to 12729 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0058] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12310 to 12609 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12310 to 12609 of SEQ ID NO: 2, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12310 to 12609 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12310 to 12609 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence of positions 12310 to 12609 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0059] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12460 to 12759 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12460 to 12759 of SEQ ID NO: 2, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12460 to 12729 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12460 to 12759 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12460 to 12759 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0060] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12460 to 12729 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12460 to 12729 of SEQ ID NO: 2, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12460 to 12729 of SEQ ID NO: 2, or it consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12460 to 12729 of SEQ ID NO: 2, or it consists of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence of positions 12460 to 12729 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0061] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12577 to 12909 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12577 to 12909 of SEQ ID NO: 2, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12577 to 12909 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12577 to 12909 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12577 to 12909 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0062] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12610 to 12909 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12610 to 12909 of SEQ ID NO: 2, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 nucleotides are modified in the sequence of positions 12610 to 12909 of SEQ ID NO: 2, or consists of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region comprises the sequence of positions 12610 to 12909 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12610 to 12909 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0063] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12610 to 12759 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12610 to 12759 of SEQ ID NO: 2, or a sequence in which 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 nucleotides are modified in the sequence at positions 12610 to 12759 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12610 to 12759 of SEQ ID NO: 2, or is composed of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12610 to 12759 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0064] In one embodiment, the sequence encoding a portion of the CTT region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 12760 to 12909 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12760 to 12909 of SEQ ID NO: 2, or a sequence in which 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides are modified in the sequence at positions 12760 to 12909 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding a portion of the CTT region contains the sequence at positions 12760 to 12909 of SEQ ID NO: 2, or is composed of the above sequence. The sequence encoding a part of the CTT region may have a sequence different from the sequence at positions 12760 to 12909 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0065] In one embodiment, the truncated PC1 is a membrane-localized polypeptide. A membrane-localized polypeptide refers to a polypeptide that is localized to the cell membrane when expressed in a cell.

[0066] In one embodiment, the truncated PC1 contains at least a portion of the stem region of PC1 in addition to the CTT region or a portion thereof. In one embodiment, the truncated PC1 contains at least a portion of the stem region of PC1 and at least one transmembrane region in addition to the CTT region. In one embodiment, the truncated PC1 contains a signal sequence in addition to the CTT region. In one embodiment, the truncated PC1 contains a signal sequence and at least one transmembrane region in addition to the CTT region.

[0067] In one embodiment, at least a portion of the stem region is composed of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids, for example, 25 or 26 amino acids. In one embodiment, at least a portion of the stem region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 3049 to 3074 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, at least a portion of the stem region contains the sequence of positions 3049 to 3074 of SEQ ID NO. 1, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of positions 3049 to 3074 of SEQ ID NO. 1, or consists of the above sequence. In one embodiment, at least a portion of the stem region contains the sequence of positions 3049 to 3074 of SEQ ID NO. 1, or consists of the above sequence.

[0068] The sequence of the polynucleotide encoding at least a portion of the stem region is not particularly limited as long as it encodes at least a portion of the stem region described in this specification. In one embodiment, the sequence encoding at least a portion of the stem region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more than 99% with the sequence at positions 3049 to 3074 of sequence number 1, or is composed of the above sequence. In one embodiment, the sequence encoding at least a portion of the stem region contains a sequence encoding the sequence at positions 3049 to 3074 of sequence number 1, or a sequence in which 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence at positions 3049 to 3074 of sequence number 1, or is composed of the above sequence. In one embodiment, the sequence encoding at least a portion of the stem region contains a sequence encoding the sequence at positions 3049 to 3074 of sequence number 1, or is composed of the above sequence.

[0069] In one embodiment, the sequence encoding at least a portion of the stem region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 9145 to 9222 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding at least a portion of the stem region contains the sequence at positions 9145 to 9222 of SEQ ID NO: 2, or is modified from the sequence at positions 9145 to 9222 of SEQ ID NO: 2 by 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 nucleotides, or is composed of the above sequence. In one embodiment, the sequence encoding at least a portion of the stem region contains the sequence at positions 9145 to 9222 of SEQ ID NO: 2, or is composed of the above sequence. The sequence encoding at least a portion of the stem region may have a sequence different from the sequence at positions 9145 to 9222 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0070] The transmembrane region is a polypeptide region that penetrates the cell membrane as a lipid bilayer. In the truncated PC1 of the present invention, the transmembrane region can be a transmembrane region from any protein as long as the truncated PC1 can be fixed to the cell membrane. As the transmembrane region, in addition to the transmembrane region of PC1, for example, the α chain and β chain of the T cell receptor (TCR), CD3ε, CD4, CD5, CD7, CD8, CD9, CD16, CD22, CD27, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD95, CD134, CD137, CD154, PKD2, VSV-G (Vesicular stomatitis virus G protein), PLAP (placental alkaline phosphatase) transmembrane region can also be listed.

[0071] In one embodiment, at least one transmembrane region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 transmembrane regions.

[0072] PC1 has 11 transmembrane regions (referred to as TM1, TM2, TM3, TM4, TM5, TM6, TM7, TM8, TM9, TM10, and TM11 from the N-terminus). In one embodiment, at least one transmembrane region contains at least one of the transmembrane regions of PC1 or a portion thereof. In one embodiment, at least one transmembrane region contains TM1 to TM11, TM2 to TM11, TM3 to TM11, TM4 to TM11, TM5 to TM11, TM6 to TM11, TM7 to TM11, TM8 to TM11, TM9 to TM11, TM10 to TM11, or TM11 of PC1. In one embodiment, at least one transmembrane region contains TM1 to TM11 or TM6 to TM11.

[0073] In the present specification, when "at least one transmembrane region" contains two or more transmembrane regions, the amino acid sequence of "at least one transmembrane region" also contains the amino acid sequence of the extracellular region and / or the intracellular region between the transmembrane regions. In one embodiment, at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 3075 to 4101 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence of positions 3075 to 4101 of SEQ ID NO: 1, or 1 to 300, 1 to 290, 1 to 280, 1 to 270, 1 to 260, 1 to 250, 1 to 240, 1 to 230, 1 to 220, 1 to 210, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 15 ... 1-140, 1-130, 1-120, 1-110, 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 amino acid sequences, or consisting of the above sequences. In one embodiment, at least one transmembrane region contains the sequence of positions 3075 to 4101 of SEQ ID NO: 1, or consists of the above sequence.

[0074] In one embodiment, at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence at positions 3602 to 4101 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence of positions 3602 to 4101 of SEQ ID NO: 1, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of positions 3602 to 4101 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence of positions 3602 to 4101 of SEQ ID NO: 1, or consists of the above sequence.

[0075] In one embodiment, at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence at positions 244 to 264 of SEQ ID NO: 21, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence.

[0076] In one embodiment, at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 174 to 190 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence at positions 174 to 190 of SEQ ID NO: 24, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 174 to 190 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, at least one transmembrane region contains the sequence at positions 174 to 190 of SEQ ID NO: 24, or is composed of the above sequence.

[0077] The sequence of the polynucleotide encoding the transmembrane region is not particularly limited as long as it encodes the transmembrane region described in the present specification. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of positions 3075 to 4101 of SEQ ID NO: 1, or consists of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region comprises the sequence encoding positions 3075 to 4101 of SEQ ID NO. 1, or 1 to 300, 1 to 290, 1 to 280, 1 to 270, 1 to 260, 1 to 250, 1 to 240, 1 to 230, 1 to 220, 1 to 210, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150 of the sequence encoding positions 3075 to 4101 of SEQ ID NO. 1 are modified. In one embodiment, the sequence encoding at least one transmembrane region comprises a sequence encoding the sequence of positions 3075 to 4101 of SEQ ID NO: 1, or consists of the above sequence.

[0078] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence at positions 3602 to 4101 of SEQ ID NO: 1, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence encoding positions 3602 to 4101 of SEQ ID NO: 1, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of positions 3602 to 4101 of SEQ ID NO: 1, or consists of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding the sequence at positions 3602 to 4101 of SEQ ID NO: 1, or consists of the above sequence.

[0079] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding the sequence at positions 244 to 264 of SEQ ID NO: 21, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding the sequence at positions 244 to 264 of SEQ ID NO: 21, or is composed of the above sequence.

[0080] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 174 to 190 of SEQ ID NO: 24, or consists of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding the sequence at positions 174 to 190 of SEQ ID NO: 24, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 174 to 190 of SEQ ID NO: 24, or consists of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains a sequence encoding the sequence at positions 174 to 190 of SEQ ID NO: 24, or consists of the above sequence.

[0081] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 9223 to 12303 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 9223 to 12303 of SEQ ID NO: 2, or 1 to 900, 1 to 800, 1 to 700, 1 to 600, 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1-130, 1-120, 1-110, 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotide sequences, or consisting of the above sequences. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence of positions 9223 to 12303 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding at least one transmembrane region may have a sequence different from the sequence of positions 9223 to 12303 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0082] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 10804 to 12303 of SEQ ID NO: 2, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 10804 to 12303 of SEQ ID NO: 2, or 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120 of the sequence at positions 10804 to 12303 of SEQ ID NO: 2 is modified. , 1-110, 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotide sequences, or consisting of the above sequences. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence of positions 10804 to 12303 of SEQ ID NO: 2, or consists of the above sequence. The sequence encoding at least one transmembrane region may have a sequence different from the sequence of positions 10804 to 12303 of SEQ ID NO: 2 due to the degeneracy of the genetic code.

[0083] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 730 to 792 of SEQ ID NO: 22, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 730 to 792 of SEQ ID NO: 22, or a sequence in which 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides are modified in the sequence at positions 730 to 792 of SEQ ID NO: 22, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 730 to 792 of SEQ ID NO: 22, or is composed of the above sequence. The sequence encoding at least one transmembrane region may have a sequence different from the sequence at positions 730 to 792 of SEQ ID NO: 22 due to the degeneracy of the genetic code.

[0084] In one embodiment, the sequence encoding at least one transmembrane region contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence at positions 520 to 570 of SEQ ID NO: 25, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 520 to 570 of SEQ ID NO: 25, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides are modified in the sequence at positions 520 to 570 of SEQ ID NO: 25, or is composed of the above sequence. In one embodiment, the sequence encoding at least one transmembrane region contains the sequence at positions 520 to 570 of SEQ ID NO: 25, or is composed of the above sequence. The sequence encoding at least one transmembrane region may have a sequence different from the sequence at positions 520 to 570 of SEQ ID NO: 25 due to the degeneracy of the genetic code.

[0085] The signal sequence can be a sequence from any protein as long as it can localize the truncated PC1 containing the sequence to the cell membrane. As a signal sequence, in addition to the sequence from PC1, the sequence from Igκ chain, CD16, CD95, CD116, CD137 or PKD2 can also be listed. In addition, the known sequence (The EMBO Journal vol.10 no.13 pp.4033-4039, 1991) that is known to localize proteins to the cell membrane, such as the CAAX motif, can be used. In one embodiment, the signal sequence contains at least a portion of the signal sequence of PC1, Igκ chain, CD16, CD95, CD116, CD137 or PKD2.

[0086] In one embodiment, the signal sequence comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 1 to 21 of SEQ ID NO: 19, or is composed of the above sequence. In one embodiment, the signal sequence comprises a sequence at positions 1 to 21 of SEQ ID NO: 19, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 21 of SEQ ID NO: 19, or is composed of the above sequence. In one embodiment, the signal sequence comprises a sequence at positions 1 to 21 of SEQ ID NO: 19, or is composed of the above sequence.

[0087] In one embodiment, the signal sequence contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 1 to 16 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, the signal sequence contains the sequence at positions 1 to 16 of SEQ ID NO: 21, or is composed of a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 16 of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, the signal sequence contains the sequence at positions 1 to 16 of SEQ ID NO: 21, or is composed of the above sequence.

[0088] In one embodiment, the signal sequence contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, the signal sequence contains the sequence at positions 1 to 25 of SEQ ID NO: 24, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, the signal sequence contains the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence.

[0089] The sequence of the polynucleotide encoding the signal sequence is not particularly limited as long as it encodes the signal sequence described in this specification. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more than 99% with the sequence at positions 1 to 21 of sequence number 19, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding positions 1 to 21 of sequence number 19, or a sequence in which 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 21 of sequence number 19, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding positions 1 to 21 of sequence number 19, or is composed of the above sequence.

[0090] In one embodiment, the sequence encoding the signal sequence contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 1 to 16 of sequence number 21, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding positions 1 to 16 of sequence number 21, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 16 of sequence number 21, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding positions 1 to 16 of sequence number 21, or is composed of the above sequence.

[0091] In one embodiment, the sequence encoding the signal sequence contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding the sequence at positions 1 to 25 of SEQ ID NO: 24, or a sequence in which 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains a sequence encoding the sequence at positions 1 to 25 of SEQ ID NO: 24, or is composed of the above sequence.

[0092] In one embodiment, the sequence encoding the signal sequence contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence at positions 1 to 63 of sequence number 20, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 63 of sequence number 20, or is modified with 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides in the sequence at positions 1 to 63 of sequence number 20, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 63 of sequence number 20, or is composed of the above sequence. The sequence encoding the signal sequence may have a sequence different from the sequence at positions 1 to 63 of sequence number 20 due to the degeneracy of the genetic code.

[0093] In one embodiment, the sequence encoding the signal sequence contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence at positions 1 to 48 of sequence number 22, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 48 of sequence number 22, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides are modified in the sequence at positions 1 to 48 of sequence number 22, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 48 of sequence number 22, or is composed of the above sequence. The sequence encoding the signal sequence may have a sequence different from the sequence at positions 1 to 48 of sequence number 22 due to the degeneracy of the genetic code.

[0094] In one embodiment, the sequence encoding the signal sequence contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more with the sequence at positions 1 to 75 of sequence number 25, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 75 of sequence number 25, or a sequence in which 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 nucleotides are modified in the sequence at positions 1 to 75 of sequence number 25, or is composed of the above sequence. In one embodiment, the sequence encoding the signal sequence contains the sequence at positions 1 to 75 of sequence number 25, or is composed of the above sequence. The sequence encoding the signal sequence may have a sequence different from the sequence at positions 1 to 75 of sequence number 25 due to the degeneracy of the genetic code.

[0095] When the polypeptide of the present invention contains two or more parts such as a signal sequence, at least one transmembrane region, and a CTT region, the parts can be connected by a linker. As the linker, a peptide linker containing amino acids such as glycine, serine, arginine, alanine, and proline can be listed.

[0096] When the truncated PC1 contains two or more parts (and a linker if necessary), a polynucleotide encoding the truncated PC1 can be prepared by ligating the polynucleotides encoding the respective parts (and a linker if necessary) in frame.

[0097] In one embodiment, the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 5, or consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 5, or 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 196, 1 ​​to 208, 1 to 210, 1 to 221, 1 to 231, 1 to 241, 1 to 252, 1 to 264, 1 to 275, 1 to 286, 1 to 297, 2 to 301, 2 to 313, 2 to 329, 2 to 331, 2 to 343, 2 to 354, 2 to 365, 2 to 379, 2 to 381, 2 to 399, 3 to 401, 3 to 413, 2 to 429, 2 to 431, 2 to 443, 2 to 459, 2 to 461, 2 to 471, 2 to 481, 2 to 49 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 amino acid sequences, or consisting of the above sequences. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 5, or consists of the above sequence.

[0098] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 5, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 5, or a sequence of SEQ ID NO: 5 in which 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 amino acid sequences, or consisting of the above sequences. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 5, or consists of the above sequence.

[0099] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 6, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 6, or 1 to 1200, 1 to 1100, 1 to 1000, 1 to 900, 1 to 800, 1 to 700, 1 to 600, 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 196, 1 ​​to 185, 1 to 197, 1 to 186, 1 to 187, 1 to 198, 1 to 199, 1 to 201 1-130, 1-120, 1-110, 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 6, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 6 due to the degeneracy of the genetic code.

[0100] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 19, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO:19, or a sequence in which 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO:19, or consists of the above sequence. In one embodiment, the truncated PC1 contains the sequence of SEQ ID NO: 19, or consists of the above sequence.

[0101] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 19, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 19, or a sequence in which 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4 or 1, 2 or 3 amino acids are modified from the sequence of SEQ ID NO: 19, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding the sequence of SEQ ID NO: 19, or consists of the above sequence.

[0102] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 20, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 20, or 1 to 700, 1 to 600, 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110 of the sequence of SEQ ID NO: 20 is modified. , 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 20, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 20 due to the degeneracy of the genetic code.

[0103] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 21, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 21, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 21, or a sequence consisting of the above sequence is formed. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 21, or a sequence consisting of the above sequence.

[0104] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 21, or is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 21, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 21, or the sequence is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 21, or the sequence is composed of the above sequence.

[0105] In one embodiment, the sequence encoding the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 22, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 22, or 1 to 700, 1 to 600, 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110 of the sequence of SEQ ID NO: 22 is modified. , 1-100, 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 22, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 22 due to the degeneracy of the genetic code.

[0106] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 24, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 24, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 24, or the sequence consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 24, or the sequence consists of the above sequence.

[0107] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 24, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 24, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 24, or the sequence consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 24, or the sequence consists of the above sequence.

[0108] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 25, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 25, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 218, 1 to 220, 1 to 231, 1 to 232, 1 to 233, 1 to 234, 1 to 236, 1 to 237, 1 to 238, 1 to 239, 1 to 241, 1 to 250, 1 to 251 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 25, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of SEQ ID NO: 25 due to the degeneracy of the genetic code.

[0109] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 36, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 36, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 36, or a sequence consisting of the above sequence is used. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 36, or a sequence consisting of the above sequence.

[0110] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 36, or is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 36, or a sequence in which 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 36, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 36, or consists of the above sequence.

[0111] In one embodiment, the sequence encoding the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 37, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 37, or 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100 of the sequence of SEQ ID NO: 37 is modified. , 1-95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 37, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 37 due to the degeneracy of the genetic code.

[0112] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 38, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 38, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 38, or a sequence consisting of the above sequence is formed. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 38, or a sequence consisting of the above sequence.

[0113] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 38, or is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 38, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 38, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 38, or consists of the above sequence.

[0114] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 39, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 39, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 228, 1 to 230, 1 to 240, 1 to 251, 1 to 261, 1 to 271, 1 to 282, 1 to 291, 2 to 303, 1 to 314, 1 to 325, 1 to 336, 1 to 347, 1 to 358, 1 to 369, 1 to 371 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 39, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 39 due to the degeneracy of the genetic code.

[0115] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 40, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 40, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 40, or a sequence consisting of the above sequence is formed. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 40, or a sequence consisting of the above sequence.

[0116] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 40, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 40, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 40, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 40, or consists of the above sequence.

[0117] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 41, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 41, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 220, 1 to 231, 1 to 240, 1 to 251, 1 to 261, 1 to 271, 1 to 281, 1 to 291, 1 to 301, 1 to 311, 1 to 322, 1 to 333, 1 to 343, 1 to 354, 1 to 365, 1 to 371 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 41, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 41 due to the degeneracy of the genetic code.

[0118] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 42, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 42, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 42, or the sequence consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 42, or the sequence consists of the above sequence.

[0119] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 42, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 42, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 42, or the sequence is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 42, or the sequence is composed of the above sequence.

[0120] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 43, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 43, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 220, 1 to 231, 1 to 241, 1 to 250, 1 to 261, 1 to 271, 1 to 281, 1 to 291, 1 to 301, 1 to 311, 1 to 322, 1 to 333, 1 to 344, 1 to 355, 1 to 366, 1 to 371 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 43, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 43 due to the degeneracy of the genetic code.

[0121] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 44, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 44, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 44, or it consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 44, or it consists of the above sequence.

[0122] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 44, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 44, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 44, or the above sequence is composed of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 44, or the above sequence is composed of the above sequence.

[0123] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 45, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 45, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 220, 1 to 231, 1 to 240, 1 to 251, 1 to 261, 1 to 271, 1 to 281, 1 to 291, 2 to 302, 1 to 313, 1 to 324, 1 to 335, 1 to 346, 1 to 357, 1 to 368, 1 to 371, 1 to 383, 1 to 394, 1 to 408, 1 to 411, 1 to 412, 1 to 425 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 45, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of SEQ ID NO: 45 due to the degeneracy of the genetic code.

[0124] In one embodiment, the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of SEQ ID NO: 46, or is composed of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 46, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 46, or the sequence consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 46, or the sequence consists of the above sequence.

[0125] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 46, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 46, or a sequence in which 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 46, or it consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 46, or it consists of the above sequence.

[0126] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 47, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 47, or 1 to 400, 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 151, 1 to 162, 1 to 173, 1 to 184, 1 to 195, 1 to 206, 1 to 217, 1 to 220, 1 to 231, 1 to 241, 1 to 250, 1 to 261, 1 to 271, 1 to 281, 1 to 291, 1 to 301, 1 to 311, 1 to 322, 1 to 333, 1 to 344, 1 to 355, 1 to 366, 1 to 371 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 47, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of SEQ ID NO: 47 due to the degeneracy of the genetic code.

[0127] In one embodiment, the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 48, or consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 48, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 48, or consists of the above sequence. In one embodiment, the truncated PC1 contains the sequence of SEQ ID NO: 48, or consists of the above sequence.

[0128] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 48, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 48, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2, or 3 amino acids are modified in the sequence of SEQ ID NO: 48, or it consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 48, or it consists of the above sequence.

[0129] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 49, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 49, or 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 49, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of SEQ ID NO: 49 due to the degeneracy of the genetic code.

[0130] In one embodiment, the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 50, or consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 50, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 50, or consists of the above sequence. In one embodiment, the truncated PC1 contains the sequence of SEQ ID NO: 50, or consists of the above sequence.

[0131] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 50, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 50, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 50, or it consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 50, or it consists of the above sequence.

[0132] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 51, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 51, or 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 51, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 51 due to the degeneracy of the genetic code.

[0133] In one embodiment, the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 52, or consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 52, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 52, or consists of the above sequence. In one embodiment, the truncated PC1 contains the sequence of SEQ ID NO: 52, or consists of the above sequence.

[0134] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 52, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 52, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 52, or it consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 52, or it consists of the above sequence.

[0135] In one embodiment, the sequence encoding the truncated PC1 contains a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 53, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 53, or 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of sequence number 53, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of sequence number 53 due to the degeneracy of the genetic code.

[0136] In one embodiment, the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 54, or consists of the above sequence. In one embodiment, the truncated PC1 comprises the sequence of SEQ ID NO: 54, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 54, or consists of the above sequence. In one embodiment, the truncated PC1 contains the sequence of SEQ ID NO: 54, or consists of the above sequence.

[0137] In one embodiment, the sequence encoding the truncated PC1 contains a sequence encoding a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more to the sequence of sequence number 54, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding SEQ ID NO: 54, or a sequence in which 1 to 100, 1 to 95, 1 to 90, 1 to 85, 1 to 80, 1 to 75, 1 to 70, 1 to 65, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 35, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, or 1, 2 or 3 amino acids are modified in the sequence of SEQ ID NO: 54, or it consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises a sequence encoding a sequence of SEQ ID NO: 54, or it consists of the above sequence.

[0138] In one embodiment, the sequence encoding the truncated PC1 comprises a sequence having a sequence identity of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or more to the sequence of SEQ ID NO: 55, or consists of the above sequence. In one embodiment, the sequence encoding the truncated PC1 comprises the sequence of SEQ ID NO: 55, or 1 to 300, 1 to 200, 1 to 190, 1 to 180, 1 to 170, 1 to 160, 1 to 150, 1 to 140, 1 to 130, 1 to 120, 1 to 110, 1 to 100, 1 to 95, 1-90, 1-85, 1-80, 1-75, 1-70, 1-65, 1-60, 1-55, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4 or 1, 2 or 3 nucleotides, or consisting of the above sequence. In one embodiment, the sequence encoding the truncated PC1 contains the sequence of SEQ ID NO: 55, or consists of the above sequence. The sequence encoding the truncated PC1 may have a sequence different from the sequence of SEQ ID NO: 55 due to the degeneracy of the genetic code.

[0139] In the present specification, at least a part of a region or sequence may be any part of the region or sequence, or may be the entire region or sequence.

[0140] In the present specification, “comprising” a prescribed sequence is used to mean including a sequence in which one or more amino acids (in the case of an amino acid sequence) or nucleotides (in the case of a nucleotide sequence) are added to the prescribed sequence, as well as a sequence consisting of the prescribed sequence.

[0141] Regarding amino acid sequences or nucleotide sequences, sequence identity refers to the ratio of identical amino acid residues or bases between two sequences aligned in the best state (the state with the highest degree of identity). Sequence identity can be calculated by the following formula: sequence identity (%) = [(identical amino acid residues or bases between two sequences) / (alignment length)] × 100. Sequence identity can be calculated using programs such as FASTA and BLAST.

[0142] The modification of amino acids and nucleotides includes deletion, substitution, insertion and addition of amino acids and nucleotides. The modification may be any one of deletion, substitution, insertion and addition, or a combination of two or more of these.

[0143] The cyst formation inhibitory effect can be confirmed by a person skilled in the art using a suitable method. For example, the cyst formation model described in the embodiments or the literature (Yan B. et al., J Am Soc Nephrol 19: 1300-1310, 2008) can be used. The MDCK (Madin-Darby canine kidney) cells from dog kidney tubular epithelial cells are three-dimensionally cultured on a collagen gel, and when stimulated with forskolin, cyst formation can be observed. When EGF is added in addition to forskolin, the time until cyst formation can be shortened (Molecular Cell 6: 1267-12732000). When the MDCK cells expressing the truncated PC1 by introducing a polynucleotide encoding the truncated PC1 or a vector containing the truncated PC1 can inhibit cyst formation compared to the control, it can be judged that the truncated PC1 has a cyst formation inhibitory effect. The truncated PC1 of the present invention can, for example, inhibit cyst formation by at least 20%, 30%, 40%, 50%, 60%, 70% or 80% compared to a control.

[0144] By administering a polynucleotide containing a sequence encoding a truncated PC1 or a vector containing the same to a subject, the truncated PC1 can be expressed in the subject. The polynucleotide may be DNA or RNA, and may contain one or more non-natural nucleotides.

[0145] Vector refers to a substance that can deliver a polynucleotide with a desired sequence to a cell. The vector can be a viral vector or a non-viral vector. As a viral vector, retrovirus, slow virus, adenovirus, adeno-associated virus (AAV), herpes simplex virus (HSV), vaccinia virus, Sendai virus or measles virus vectors can be listed. As a non-viral vector, plasmid vectors, liposome vectors and artificial chromosomes (such as YAC, BAC, PAC) can be listed. Each vector can be made according to a conventional method.

[0146] The vector may contain one or more regulatory sequences that can regulate the expression of the sequence encoding the truncated PC1. As regulatory sequences, other expression control elements such as promoters, enhancers, polyadenylation signals, post-transcriptional regulatory elements (PRE) can be listed. The promoter can be a constitutive promoter, an inducible promoter, or a tissue or cell specific promoter. As promoters, CMV (Cytomegalovirus) promoter, PGK (Phosphoglycerate kinase) promoter, EF1α (Elongation factor 1-alpha) promoter, CAG promoter, SV40 promoter, and MSCV promoter can be listed. As polyadenylation signals, the polyadenylation signal of SV40, the polyadenylation signal of the bovine growth hormone gene, and the globulin polyadenylation signal can be listed. Examples of PRE include WPRE, adenovirus tripartite leadersequence, cytomegalovirus intron A, and HSP70 5'UTR (untranslated region).

[0147] The vector may contain an origin of replication (ori) for its own replication. In addition, it may contain a marker for selecting cells containing the vector. As a selection marker, genes that confer resistance to agents such as neomycin, kanamycin, puromycin, hygromycin, zeocin, and ampicillin may be listed.

[0148] In one embodiment, the vector is an AAV vector. There are many serotypes of AAV, such as AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV-rh10, AAV-DJ and AAV Anc80. The AAV vector can be in a natural form or in a recombinant form modified by capsid protein and the like. For example, the AAV vector can be prepared by introducing an AAV vector plasmid containing a sequence encoding a truncated PC1 (or a truncated PC1 coding sequence configured downstream of a promoter) and ITRs (inverted terminal repeats) at both ends thereof together with an AAV auxiliary plasmid containing the Rep gene and the Cap gene required for AAV replication and particle formation and an adenovirus auxiliary plasmid having the auxiliary gene of adenovirus required for AAV proliferation into a packaging cell. As packaging cells, 293T cells, 293 cells, HeLa cells, COS1 cells, COS7 cells, etc. can be listed. Virus particles released from packaging cells can be recovered from the culture supernatant of packaging cells by purification methods such as centrifugation, filter filtration, column purification, etc.

[0149] In one embodiment, the vector is a lentiviral vector. Examples of lentiviral vectors include HIV (human immunodeficiency virus) (e.g., HIV-1 and HIV-2), SIV (simian immunodeficiency virus), FIV (feline immunodeficiency virus), MVV (Maedi-Visna virus), EV1 (Maedi-Visna-like virus), EIAV (equine infectious anemia virus), and CAEV (caprine arthritis encephalitis virus). Lentiviral vectors can be prepared, for example, by introducing a viral vector plasmid containing a sequence encoding a truncated PC1 (or a truncated PC1 coding sequence configured downstream of a promoter) and LTRs (long terminal repeats) at both ends thereof (5'LTR and 3'LTR) and a packaging signal into a packaging cell together with one or more plasmid vectors expressing viral structural proteins such as Gag, Pol, and Env, or into packaging cells expressing these structural proteins. The viral vector can be pseudotyped, for example, one or more plasmid vectors expressing envelope proteins such as vesicular stomatitis virus G protein (VSV-G) can also be introduced into packaging cells. As packaging cells, 293T cells, 293 cells, HeLa cells, COS1 cells, COS7 cells, etc. can be listed. Viral particles released from packaging cells can be recovered from the culture supernatant of packaging cells by purification methods such as centrifugation, filter filtration, column purification, etc.

[0150] In one embodiment, the polynucleotide containing a sequence encoding a truncated PC1 is RNA. In this embodiment, the polynucleotide may contain a 5' cap structure, a 5' untranslated region (UTR), a truncated PC1 coding sequence, a 3'UTR and a poly A sequence. The polynucleotide can be produced, for example, by in vitro transcription using plasmid DNA as a template. In order to be delivered into cells, the polynucleotide can be encapsulated in lipid particles or polymer particles and then administered.

[0151] By expressing the truncated PC1 of the present invention in an object or administering the truncated PC1 of the present invention to an object, PKD1-related diseases can be treated. PKD1-related diseases refer to diseases caused by loss of PC1 function due to PKD1 gene mutation. PKD1-related diseases include cystic diseases, hypertension, intracranial aneurysms, colorectal diverticula, heart valve regurgitation, and kidney stones. In one embodiment, PKD1-related diseases are cystic diseases. As cystic diseases, polycystic kidney disease (polycystickidney disease, PKD), polycystic liver disease (polycystic liver disease, PLD), nephrotic syndrome (NPHP), Bardet-Biedl syndrome (BBS), Meckel syndrome (MKS), Joubert syndrome (JBTS), oral facial digital syndrome (Oral facial digital syndrome, OFD) or pancreatic cysts (pancreatic cysts) can be listed. In one embodiment, the cystic disease is PKD. PKD includes autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

[0152] In one embodiment, PKD is ADPKD. ADPKD is a hereditary disease with PKD1 and PKD2 as pathogenic genes, and 85% of patients are caused by abnormal PKD1 gene. PC1 and PC2 regulate Ca 2+ It is believed that loss of function of PC1 or PC2 due to mutation of the PKD1 or PKD2 gene leads to cyst formation.

[0153] Treatment of a PKD1-related disease includes ameliorating or inhibiting one or more symptoms or findings of the disease. For example, treatment of ADPKD includes inhibiting the increase in kidney volume and inhibiting the decline in kidney function in ADPKD.

[0154] The polynucleotide, polypeptide or vector is administered to the subject in an amount (referred to as an effective amount in this specification) that can exert the desired effect (e.g., the therapeutic effect of PKD1-related diseases). The dosage can be appropriately selected according to the age, weight, health status, etc. of the subject. In the case of AAV vectors, for example, about 10 μg of the drug per kg of body weight can be administered. 9 ~10 15 vg (vector genome), 10 10 ~10 14 vg or 1010 ~10 13 In the case of a lentiviral vector, for example, about 10 4 ~10 10 TU (transducing unit). In the case of non-viral vectors, about 0.01 to 100 mg / kg can be administered per 1 kg of body weight. Administration can be performed daily, once a day or several days, once a week or several weeks, once a month or several months, or once a few years or once a lifetime. The daily dose can be administered once or divided into multiple doses (for example, 2 to 4 doses).

[0155] The method of administration can be appropriately selected according to the age, weight, health status, etc. of the subject. The method of administration can be oral administration or parenteral administration, preferably parenteral administration. Examples of parenteral administration include subcutaneous administration, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration, femoral artery-renal artery catheter administration, ureteral retrograde administration, etc.

[0156] In addition to polynucleotides, polypeptides or carriers, the pharmaceutical composition may also contain sterile water, physiological saline, stabilizers, excipients, antioxidants, buffers, preservatives, surfactants, chelating agents, binders and other pharmaceutically acceptable carriers or additives. The dosage form is not limited, for example, it is an injection. Injections include solution injections, suspension injections, emulsion injections and injections prepared for use (such as freeze-dried injections). The pharmaceutical composition can be provided in the form of a kit, which may also contain a buffer used for preparation, instructions for use, etc.

[0157] The subject may be a mammal, such as a human or a non-human mammal. Examples of non-human mammals include mice, rats, rabbits, cats, dogs, sheep, pigs, horses, cows, and monkeys. In one embodiment, the subject is a human.

[0158] Exemplary embodiments of the present invention are described below. [1]

[0160] A polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1) having a cyst formation inhibitory effect, wherein the truncated PC1 comprises a C-terminal tail (CTT) region of PC1 or a part thereof. [2]

[0162] The polynucleotide according to item 1 above, wherein the truncated PC1 contains the CTT region of PC1. [3]

[0164] The polynucleotide according to item 1 above, wherein the truncated PC1 contains a part of the CTT region of PC1. [4]

[0166] The polynucleotide according to any one of 1 to 3 above, wherein the truncated PC1 lacks at least a part of the extracellular N-terminal region of PC1. [5]

[0168] The polynucleotide according to any one of 1 to 4 above, wherein the truncated PC1 lacks the entire extracellular N-terminal region of PC1. [6]

[0170] The polynucleotide according to any one of 1 to 5 above, wherein the truncated PC1 is a membrane-localized polypeptide. [7]

[0172] A polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1), wherein the truncated PC1 is a membrane-localized polypeptide comprising a C-terminal tail (CTT) region of PC1 or a portion thereof. [8]

[0174] The polynucleotide according to item 7 above, wherein the truncated PC1 contains the CTT region of PC1. [9]

[0176] The polynucleotide according to item 7 above, wherein the truncated PC1 contains a part of the CTT region of PC1.

[10]

[0178] The polynucleotide according to any one of 1 to 9 above, wherein the truncated PC1 further comprises at least a part of the stem region of PC1.

[11]

[0180] The polynucleotide according to item 10 above, wherein the truncated PC1 further comprises at least one transmembrane region.

[12]

[0182] The polynucleotide according to any one of 1 to 9 above, wherein the truncated PC1 further comprises a signal sequence.

[13]

[0184] The polynucleotide according to item 12 above, wherein the truncated PC1 further comprises at least one transmembrane region.

[14]

[0186] The polynucleotide according to any one of 1 to 13 above, wherein the CTT region consists of a sequence having a sequence identity of 90% or more to the sequence of SEQ ID NO: 3.

[15]

[0188] The polynucleotide according to any one of 1 to 14 above, wherein the CTT region consists of the sequence of SEQ ID NO: 3.

[16]

[0190] The polynucleotide according to any one of 1 to 14 above, wherein the CTT region consists of the sequence of positions 3 to 202 of SEQ ID NO: 3.

[17]

[0192] The polynucleotide according to any one of 1 to 16 above, wherein a portion of the CTT region contains at least a portion of a sequence having a sequence identity of 90% or more to the sequence of positions 4154 to 4303 of SEQ ID NO: 1.

[18]

[0194] The polynucleotide according to any one of 1 to 17 above, wherein a portion of the CTT region contains at least a portion of the sequence of positions 4154 to 4303 of SEQ ID NO: 1.

[19]

[0196] The polynucleotide according to any one of 1 to 18 above, wherein a portion of the CTT region contains a sequence having a sequence identity of 90% or more to the sequence at positions 4204 to 4243 of SEQ ID NO: 1.

[20]

[0198] The polynucleotide according to any one of 1 to 19 above, wherein a portion of the CTT region contains the sequence of positions 4204 to 4243 of SEQ ID NO: 1. [twenty one]

[0200] The polynucleotide according to any one of 1 to 20 above, wherein a portion of the CTT region contains a sequence having a sequence identity of 90% or more to the sequence at positions 4204 to 4253 of SEQ ID NO: 1. [twenty two]

[0202] The polynucleotide according to any one of 1 to 21 above, wherein a portion of the CTT region contains the sequence of positions 4204 to 4253 of SEQ ID NO: 1. [twenty three]

[0204] The polynucleotide according to any one of 1 to 22 above, wherein the length of the part of the CTT region is 150 amino acids or less. [twenty four]

[0206] A polynucleotide according to any one of 11 and 13 to 23 above, wherein at least one transmembrane region is selected from the transmembrane region or a portion thereof of PC1, the α chain or β chain of the T cell receptor, CD3ε, CD4, CD5, CD7, CD8, CD9, CD16, CD22, CD27, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD95, CD134, CD137, CD154, PKD2, VSV-G or PLAP.

[25]

[0208] The polynucleotide according to any one of 11 and 13 to 24 above, wherein at least one transmembrane region consists of a sequence having a sequence identity of 90% or more to the sequence at positions 3075 to 4101 of SEQ ID NO: 1.

[26]

[0210] The polynucleotide according to item 25 above, wherein at least one transmembrane region consists of the sequence of positions 3075 to 4101 of SEQ ID NO: 1.

[27]

[0212] The polynucleotide according to any one of 11 and 13 to 24 above, wherein at least one transmembrane region consists of a sequence having a sequence identity of 90% or more to the sequence at positions 3602 to 4101 of SEQ ID NO: 1.

[28]

[0214] The polynucleotide according to item 27 above, wherein at least one transmembrane region consists of the sequence of positions 3602 to 4101 of SEQ ID NO: 1.

[29]

[0216] The polynucleotide according to any one of 11 and 13 to 24 above, wherein at least one transmembrane region consists of a sequence having a sequence identity of 90% or more to the sequence at positions 244 to 264 of SEQ ID NO: 22.

[30]

[0218] The polynucleotide according to item 29 above, wherein at least one transmembrane region consists of the sequence of positions 244 to 264 of SEQ ID NO: 22.

[31]

[0220] The polynucleotide according to any one of 11 and 13 to 24 above, wherein at least one transmembrane region consists of a sequence having a sequence identity of 90% or more to the sequence at positions 174 to 190 of SEQ ID NO: 24.

[32]

[0222] The polynucleotide according to item 31 above, wherein at least one transmembrane region consists of the sequence of positions 174 to 190 of SEQ ID NO:24.

[33]

[0224] The polynucleotide according to any one of items 12 to 32 above, wherein the signal sequence comprises at least a portion of a signal sequence of PC1, Igκ chain, CD16, CD95, CD116, CD137, or PKD2.

[34]

[0226] The polynucleotide according to any one of 12 to 33 above, wherein the signal sequence consists of a sequence having a sequence identity of 90% or more with the sequence at positions 1 to 21 of SEQ ID NO: 19.

[35]

[0228] The polynucleotide according to item 34 above, wherein the signal sequence consists of the sequence at positions 1 to 21 of SEQ ID NO:19.

[36]

[0230] The polynucleotide according to any one of 12 to 33 above, wherein the signal sequence consists of a sequence having a sequence identity of 90% or more with the sequence at positions 1 to 16 of SEQ ID NO: 21.

[37]

[0232] The polynucleotide according to item 36 above, wherein the signal sequence consists of the sequence of positions 1 to 16 of SEQ ID NO: 21.

[38]

[0234] The polynucleotide according to any one of 12 to 33 above, wherein the signal sequence consists of a sequence having a sequence identity of 90% or more with the sequence at positions 1 to 25 of SEQ ID NO: 24.

[39]

[0236] The polynucleotide according to item 38 above, wherein the signal sequence consists of the sequence at positions 1 to 25 of SEQ ID NO: 24.

[40]

[0238] The polynucleotide according to any one of 1 to 39 above, wherein the truncated PC1 contains a sequence having a sequence identity of 90% or more to the sequence of SEQ ID NO: 5, 19 or 21.

[41]

[0240] The polynucleotide according to claim 40, wherein the truncated PC1 contains the sequence of sequence number 5, 19 or 21.

[42]

[0242] The polynucleotide according to any one of 1 to 41 above, comprising a sequence having a sequence identity of 90% or more to the sequence of SEQ ID NO: 6, 20 or 22.

[43]

[0244] The polynucleotide according to the above-mentioned 42, which contains the sequence of sequence number 6, 20 or 22.

[44]

[0246] The polynucleotide according to any one of 1 to 39 above, wherein the truncated PC1 contains a sequence having 90% or more sequence identity with the sequence of SEQ ID NO: 24, 36, 38, 40, 42, 44, 46, 48, 50, 52 or 54.

[45]

[0248] The polynucleotide according to claim 44, wherein the truncated PC1 contains the sequence of sequence number 24, 36, 38, 40, 42, 44, 46, 48, 50, 52 or 54.

[46]

[0250] The polynucleotide according to any one of 1 to 39, 44 and 45 above, comprising a sequence having a sequence identity of 90% or more to the sequence of SEQ ID NO: 25, 37, 39, 41, 43, 45, 47, 49, 51, 53 or 55.

[47]

[0252] The polynucleotide according to the above-mentioned 46 contains the sequence of sequence number 25, 37, 39, 41, 43, 45, 47, 49, 51, 53 or 55.

[48]

[0254] A truncated polycystin 1 (PC1) polypeptide encoded by the polynucleotide described in any one of 1 to 47 above.

[49]

[0256] A vector comprising the polynucleotide according to any one of 1 to 47 above.

[50]

[0258] The vector according to item 49 above, wherein the vector is a viral vector or a non-viral vector.

[51]

[0260] The vector according to 50 above, wherein the viral vector is a retrovirus, a lentivirus, an adenovirus, an adeno-associated virus (AAV), a herpes simplex virus (HSV), a vaccinia virus, a Sendai virus or a measles virus vector.

[52]

[0262] The vector according to item 50 above, wherein the non-viral vector is a plasmid vector, a liposome vector or an artificial chromosome.

[53]

[0264] A pharmaceutical composition for treating a PKD1-related disease, comprising the polynucleotide described in any one of 1 to 47 above, the polypeptide described in 48 above, or the vector described in any one of 49 to 52 above.

[54]

[0266] The pharmaceutical composition according to 53 above, wherein the PKD1-related disease is a cystic disease.

[55]

[0268] According to the pharmaceutical composition described in 54 above, the cystic disease is polycystic kidney disease (PKD), polycystic liver disease (PLD), nephrotic syndrome (NPHP), Bardet-Biedl syndrome (BBS), Meckel syndrome (MKS), Joubert syndrome (JBTS), oral facial digital syndrome (OFD) or pancreatic cyst.

[56]

[0270] The pharmaceutical composition according to the above 55, wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).

[57]

[0272] The pharmaceutical composition according to 56 above, wherein the PKD is ADPKD.

[58]

[0274] The polynucleotide according to any one of 1 to 47 above, the polypeptide according to 48 above, or the vector according to any one of 49 to 52 above, for use in treating a PKD1-related disease.

[59]

[0276] A method for treating a PKD1-related disease, comprising the step of administering an effective amount of the polynucleotide described in any one of 1 to 47 above, the polypeptide described in 48 above, or the vector described in any one of 49 to 52 above to a subject in need thereof.

[60]

[0278] Use of the polynucleotide described in any one of 1 to 47 above, the polypeptide described in 48 above, or the vector described in any one of 49 to 52 above in the manufacture of a medicament for treating a PKD1-related disease.

[61]

[0280] A pharmaceutical composition for inhibiting cyst formation in the kidney, comprising a polynucleotide or a vector containing the polynucleotide, wherein the polynucleotide contains a sequence encoding a truncated polycystin 1 (PC1) designed in such a way that the C-terminal tail (CTT) region of PC1 or a part thereof is localized to the cell membrane.

[62]

[0282] A pharmaceutical composition is a pharmaceutical composition for inhibiting cyst formation in the kidney, comprising a polynucleotide or a vector containing the polynucleotide, wherein the polynucleotide contains a sequence encoding a truncated polycystin 1 (PC1) containing the C-terminal tail (CTT) region or a portion thereof, and the pharmaceutical composition inhibits cyst formation by localizing the CTT region or a portion thereof to the cell membrane.

[63]

[0284] A pharmaceutical composition for inhibiting cyst formation in the kidney, comprising a truncated polycystin 1 (PC1) designed so that the C-terminal tail (CTT) region or a part of PC1 is localized to the cell membrane.

[64]

[0286] A pharmaceutical composition for inhibiting cyst formation in the kidney, comprising a truncated polycystin 1 (PC1) containing a C-terminal tail (CTT) region or a portion thereof, wherein the pharmaceutical composition inhibits cyst formation by localizing the CTT region or a portion thereof to the cell membrane.

[0287] The present invention is further described below by way of examples, but the present invention is not limited to these examples in any sense.

[0288] Example

[0289] Example 1

[0290] 1. Test methods

[0291] 1.1 Cells

[0292] MDCK (Madin-Darby canine kidney) cells derived from dog kidney tubular epithelial cells were used.

[0293] 1.2 Construction of expression vector

[0294] Polycystin 1 (PC1) and its partial regions as human PKD1 gene products shown in Table 1 were cloned from PKD1 expression plasmids (Origene Technologies) and inserted into the multiple cloning site of the episomal vector pEBMulti-Hygb vector (Fujifilm Wako Pure Chemical Industries, Ltd.). In order to promote cell membrane migration, an Igκ chain leader sequence (pDisplay TM Vector (Invitrogen)) or CD16.7 (a fusion protein containing the extracellular domain of human CD16 and the transmembrane region of human CD7 (Tsiokas 94:6965-6970 1997 PNAS)). PC1 (Arg1672fs97X) is a mutation observed in patients with autosomal dominant polycystic kidney disease. R-CTF is a sequence encoding CTF inserted in reverse into a vector and was tested as a negative control that does not express CTF.

[0295] [Table 1]

[0296]

[0297] 1.3 Introduction of expression vectors into cells and selection of cells to be introduced

[0298] The prepared plasmid vector was purified from E. coli and transferred into MDCK cells using the Neon transfection system (ThermoFisherScientific). 7 The material obtained by suspending 1 μg of the expression vector in 10 μL of a cell suspension of cells / mL was set in the Neon transfection system, and transformation was performed by electroporation under the conditions of voltage: 1150V, width: 20 milliseconds, and number: 1, and added to the culture medium (DMEM / F12 containing 10% FCS) (1 mL / well, 12-well plate). The next day, the above culture medium was replaced with 500 μg / mL of hygromycin (Lifetech Norovirus Diapan) and culture was continued for 6 to 8 days to select the cells into which the expression vector was introduced.

[0299] 1.4 Preparation and culture of collagen gel solution

[0300] 3 mg / mL PureCol (Advanced Cell Matrix Co) 74.09 mL (2.25 mg / mL), 10×MEM 10 mL, inactivated fetal bovine serum (FBS) 10 mL (10%), 1 M HEPES 2 mL (20 mM), 0.75% NaHCO 32.91 mL (26 mM) and 1 mL of sterile water were mixed and adjusted to pH 7.4 with 1 N NaOH to prepare a collagen gel solution (100 mL). 250 μL of the collagen gel solution was dispensed into each well of a 24-well plate (Corning 353047) and incubated at 37°C under CO 2 The next day, MDCK cells were mixed with 500 μL of collagen gel solution to achieve 5,000 cells / well and then overlaid. The cells were incubated at 37°C with CO 2 After solidification was confirmed, forskolin (Fujifilm Wako Pure Chemical Industries, Ltd.) and EGF (Fujifilm Wako Pure Chemical Industries, Ltd.) were added to 750 μL of DMEM / F12 medium containing 10% FBS to a final concentration of 20 mM and 20 μg / mL, respectively. Figure 3 In the experiment, hygromycin was added to the culture medium to a final concentration of 400 μg / mL and the culture medium was incubated at 37°C under CO 2 The culture medium (containing forskolin and EGF, Figure 3 The test also contained hygromycin) and the culture was continued for 8 to 12 days.

[0301] 1.5 Automatic measurement of cyst size and number using Cell Voyager CV6000 or CV8000

[0302] For 24-well plates containing cysts, bright field images (equivalent to 32 locations under a 4x objective lens per well) were taken using Cell Voyager CV6000 or CV8000 (Yokogawa) (15 images were taken at intervals of 50 μm). A single image file (MinIP) was obtained by overlaying the 15 images with minimum intensity. The cyst area and number of cysts were quantified using the analysis auxiliary software included with CV6000, and the total cyst area was calculated.

[0303] 2. Results

[0304] The empty pEBMulti-Hygb vector was used as a control to evaluate the inhibitory effects of PC1, CTF, CTT, and PC1(Arg1672fs97X) on cyst formation. Cyst formation was inhibited by PC1 and CTF, but not by CTT and PC1(Arg1672fs97X) ( Figure 3 ).

[0305] To investigate the regions necessary for inhibiting cyst formation, the empty pEBMulti-Hygb vector was used as a control, and the inhibitory effects of CTF, stem region-TM(11), TM(11), TM(11)-CTT, TLD, Igκ-TLD, CD16.7-CTT, and R-CTF on cyst formation were evaluated. Among the constructs tested, CTF, Igκ-TLD, and CD16.7-CTT had an inhibitory effect on cyst formation ( Figure 4 ). Comparison of CTF with stem region-TM(11) showed that the CTT region is necessary for inhibiting cyst formation. In addition, comparison of CTF with TM(11)-CTT and the results of Igκ-TLD and CD16.7-CTT showed that at least a portion of the stem region or at least one of the signal sequences that localize the CTT region to the cell membrane is necessary for inhibiting cyst formation.

[0306] Example 2

[0307] In order to investigate whether membrane-mobile truncated PC1 polypeptides other than CD16.7-CTT and Igκ-TLD show an inhibitory effect on cyst formation, an expression vector of a fusion protein of FAS and CTT region (FAS-CTT) (Table 3) was prepared in the same manner as in Example 1 using FAS (J._Exp._Med._Vol. 217_No. 12e20291166_2020), which is known to induce cell membrane localization. Figure 5 ) and evaluated the inhibitory effect on cyst formation. As a result, FAS-CTT and CD16.7-CTT showed the same inhibitory effect on cyst formation ( Figure 6 ).

[0308] Since the membrane localization of the CTT region is believed to be necessary for inhibiting cyst formation, the CTT core region important for inhibiting cyst formation was searched. Figure 7 The expression vectors of partial regions of the CTT region shown in Table 1 (each consisting of a part of the amino acid sequence of positions 4104 to 4303 of SEQ ID NO: 1), or fusion proteins thereof with CD16.7 or FAS (Table 3), were used to evaluate the inhibitory effect on cyst formation. The results are shown in Figure 8-1 to Figure 8-4 .

[0309]

[0310] In the case of only a partial region of the CTT region, no cyst formation inhibitory effect was observed except for CTT-dNLS. On the other hand, the fusion protein of a partial region of the CTT region with CD16.7 or FAS showed a cyst formation inhibitory effect. Among them, the cyst formation inhibitory effect of CD16.7-CTT4104-4203 and CD16.7-CTT4254-4203 was weaker than that of other polypeptides. All polypeptides except CD16.7-CTT4104-4203 and CD16.7-CTT4254-4303 have an amino acid sequence of positions 4204 to 4243 of sequence number 1. Based on the above results, it can be inferred that the entire CTT region is not necessary for inhibiting cyst formation, and at least a portion of the CTT region, such as at least a portion of positions 4154 to 4303 of sequence number 1, and in particular, a partial region of the CTT region corresponding to positions 4204 to 4243 can be included.

[0311] Example 3

[0312] 1. Test methods

[0313] 1.1 Introduction of expression vectors into cells and selection of cells to be introduced

[0314] In order to confirm the intracellular localization of the truncated PC1 polypeptide, the expression vector gene of CTF, CTT, CD16.7-CTT or FAS-CTT was transferred into MDCK cells in the same manner as in Example 1. 7 The substance obtained by suspending 1 μg of expression vector in 10 μL of cell suspension with a concentration of 10 cells / mL was set in the Neon transfection system, and transformation was carried out by electroporation under the conditions of voltage: 1150V, width: 20 milliseconds, and number: 1, and added to the culture medium (DMEM / F12 containing 10% FCS) (1 mL / well, 12-well plate). The next day, the above culture medium was replaced with 500 μg / mL hygromycin (Lifetech Norovirus Diapan), and after culturing for 5 days, 2×10 5 The cells were passaged into 12-well plates at a rate of 1 cell / well.

[0315] 1.2 Preparation of cell lysate

[0316] The MDCK cells that were passaged to a 12-well plate the day before were washed three times with PBS (cold) on ice (1 mL / well). After washing, 0.25 mg / mL of EZ-link sNHS-SS-biotin (Thermofisher Scientific) solution was added to each well (400 μL / well) and allowed to stand on ice for 30 minutes. The EZ-link sNHS-SS-biotin solution was then removed and washed three times with DMEM (×1) (Gibco) (1 mL / well). After washing, 200 μL of 1×RIPA buffer (50 mM Tris-HCl pH 7.5 / 150 mM NaCl / 0.1% SDS / 0.5% SDC / 1% Triton X-100) containing 8 M urea was added to each well, and the cells were mixed and dissolved by pipetting. This operation was performed twice to obtain 400 μL of cell lysate. After thorough mixing, use EZQ TM The protein concentration of the recovered solution was measured using a protein quantification kit (#R33200, Thermofisher Scientific). 2 μg of the total protein mass of each sample was used for whole cell analysis, and the remaining sample was used for cell surface analysis.

[0317] 1.3 LC-MS determination

[0318] 1.3.1 Preparation of samples for LC-MS analysis

[0319] To prepare samples for cell surface analysis, each sample was mixed with an equal amount of 1× RIPA buffer containing 1 M arginine and then purified using Pierce TMBiotinylated proteins were purified using streptavidin magnetic beads (#88817, Thermofisher Scientific). Specifically, each sample was stirred with the beads obtained by magnetic separation from 40 μL of bead solution and incubated at room temperature for 1 hour, followed by stirring in 200 μL of washing buffer (1×RIPA buffer containing 8 M urea and 400 mM arginine) for 1 minute for washing to bind the biotinylated sample to the beads. Afterwards, in order to wash the beads, the beads were stirred in 1 mL of washing buffer for 30 seconds and then magnetically separated and recovered, and the operation was repeated 3 times. The washed beads were suspended in a 50 mM DTT solution, incubated at room temperature for 1 hour, and magnetic separation was performed to recover the supernatant, thereby separating the protein sample from biotin. The protein sample was then subjected to alkylation using iodoacetamide at a final concentration of 250 mM (shaded and incubated at room temperature for 30 minutes with shaking). For the cell lysate of the whole cell analysis sample 2μg (total protein mass), reduction with 5mM DTT (incubation at 70°C for 15 minutes) and alkylation with 50mM iodoacetamide (shaded and incubated at room temperature for 30 minutes with shaking). After protein desalting and purification, the cell surface analysis sample and the whole cell analysis sample after reduction and alkylation were enzymatically digested at 37°C for 18 hours using trypsin / Lys-C Mix, mass spectrometry grade (#V5073, Promega, 0.025μg per sample). The peptides after enzymatic digestion were desalted and purified and provided for LC-MS analysis.

[0320] 1.3.2 LC-MS analysis

[0321] After trypsin digestion of the protein, the obtained peptides were analyzed by LC-MS. LC-MS was performed using an LC-MS system that combines a nano-HPLC device (Ultimate 3000 nanoUHPLC, Thermofisher Scientific) with a mass spectrometer (Orbitrap Eclipse, Thermofisher Scientific) equipped with a gas phase separation interface (FAIMS pro, Thermofisher Scientific). In the Nano-HPLC device, a column (stationary phase) composed of a trapping column (C18 Acclaim PepMap, Thermo Scientific) and a separation column (75μm id, 12cm long, 3μm C18 particles, Nichikyo Technos) and a 0.1% formic acid-acetonitrile system as a mobile phase were used for reverse phase chromatography by gradient analysis. The analysis was performed at a flow rate of 300nl / min, and the peptides were eluted by a linear gradient that increased the acetonitrile concentration from 4% to 35% in 48 minutes. Mass spectrometry was performed by electrospray ionization in positive ion mode. In the cell surface analysis, full scan mass spectrometry was performed within m / z375-1500, and the product ion spectrum was measured by data-dependent acquisition mode. Gas phase separation using FAIMS pro was performed under three conditions: CV (compensation voltage) = -40V, -60V, and -80V. The data obtained by LC-MS was analyzed using the analysis software Proteome Discoverer3.0 (PD3.0, Thermofisher Scientific). In protein identification, the SEQUEST search program provided by PD3.0 was used to search the Dog Reference proteome (UP000002254) of Uniprot, which includes expressed genes such as human PKD1 CTT. Quantitative analysis was performed using the label-free quantitative method Precursor Ion Quantifier provided by PD3.0. In the whole cell analysis, full scan mass spectrometry was performed within m / z495-745, and the product ion spectrum was measured by data-independent acquisition mode in which precursor ions were sequentially separated with a width of 4Da. Gas phase separation using FAIMS pro was performed at CV = -45 V. The raw data file of MS was analyzed using the analysis software DIA-NN (Ver. 1.8.1) for the Dog Reference proteome (UP000002254) of Uniprot.

[0322] 2. Results

[0323] The results of the LC-MS-based expression analysis of the truncated CTT polypeptide in MDCK cells are shown in Figure 9-1 and Figure 9-2 LC-MS analysis was performed using samples for whole-cell analysis using masses corresponding to the two peptides in the CTT region (Table 4, No. 1 and No. 2). The results confirmed the expression of all peptides of CD16.7-CTT, CTF, CTT, and FAS-CTT ( Figure 9-1 On the other hand, when LC-MS analysis was performed using samples for whole-cell analysis using peptides with masses equivalent to those in the 11th transmembrane region of two CTFs (Table 4, No. 3 and No. 4), only the expression of CTF was confirmed ( Figure 9-2 The reason why the expression of CD16.7-CTT, CTT and FAS-CTT could not be confirmed is that these polypeptides do not have Figure 9-2 The peptides shown correspond to regions.

[0324] [Table 4]

[0325]

[0326] The results of the LC-MS-based cell membrane localization analysis of the truncated CTT polypeptide in MDCK cells are shown in Figure 10-1 and 10-2 . Using the sample for cell surface analysis, LC-MS analysis was performed using masses corresponding to the two peptides in the CTT region (Table 4, No. 1 and No. 2). As a result, the expression of CD16.7-CTT and FAS-CTT could be confirmed, but the expression of CTF and CTT could not be confirmed. In addition, using the sample for cell surface analysis, LC-MS analysis was performed using masses corresponding to the two peptides in the 11th transmembrane region of CTF (Table 4, No. 5 and No. 4). As a result, CTF could be detected and its localization on the cell surface was confirmed.

[0327] Figure 9-1~2 and Figure 10-1~2 The results showed that truncated peptides other than CTT (CD16.7-CTT, CTF and FAS-CTT) were localized on the cell membrane.

[0328] [Table 2-1]

[0329]

[0330] [Table 2-2]

[0331]

[0332] [Table 2-3]

[0333]

[0334] [Table 2-4]

[0335]

[0336] [Table 2-5]

[0337]

[0338] [Table 2-6]

[0339]

[0340] [Table 2-7]

[0341]

[0342] [Table 2-8]

[0343]

[0344] [Table 2-9]

[0345]

[0346] [Table 2-10]

[0347]

[0348] [Table 2-11]

[0349]

[0350] [Table 2-12]

[0351]

[0352] [Table 2-13]

[0353]

[0354] [Table 2-14]

[0355]

[0356] [Table 2-15]

[0357]

[0358] [Table 2-16]

[0359]

[0360] [Table 2-17]

[0361]

[0362] [Table 2-18]

[0363]

[0364] [Table 2-19]

[0365]

[0366] [Table 2-20]

[0367]

[0368] [Table 5-1]

[0369]

[0370] [Table 5-2]

[0371]

[0372] [Table 5-3]

[0373]

[0374] [Table 5-4]

[0375]

[0376] [Table 5-5]

[0377]

[0378] [Table 5-6]

[0379]

[0380] [Table 5-7]

[0381]

[0382] [Table 5-8]

[0383]

Claims

1. A polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1) having a cyst formation inhibitory effect, wherein: The truncated PC1 contains the C-terminal tail (CTT) region of PC1 or a portion thereof.

2. The polynucleotide according to claim 1, wherein The truncated PC1 is a membrane-localized polypeptide.

3. A polynucleotide comprising a sequence encoding a truncated polycystin 1 (PC1), wherein: The truncated PC1 is a membrane-localized polypeptide containing the C-terminal tail (CTT) region of PC1 or a part thereof.

4. The polynucleotide according to any one of claims 1 to 3, wherein The truncated PC1 contains the CTT region of PC1.

5. The polynucleotide according to any one of claims 1 to 3, wherein The truncated PC1 contains a portion of the CTT region of PC1.

6. The polynucleotide according to any one of claims 1 to 5, wherein The truncated PC1 also contains at least a portion of the stem region of PC1.

7. The polynucleotide according to claim 6, wherein The truncated PC1 also contains at least one transmembrane region.

8. The polynucleotide according to any one of claims 1 to 5, wherein The truncated PC1 also contains a signal sequence.

9. The polynucleotide according to claim 8, wherein The truncated PC1 also contains at least one transmembrane region. 10 . A truncated polycystin 1 (PC1) polypeptide encoded by the polynucleotide according to any one of claims 1 to 9.

11. A vector comprising the polynucleotide according to any one of claims 1 to 9. 12 . A pharmaceutical composition for treating a PKD1-related disease, comprising the polynucleotide according to any one of claims 1 to 9, the polypeptide according to claim 10 or the vector according to claim 11 .

13. A pharmaceutical composition for inhibiting cyst formation in the kidney, comprising a polynucleotide or a vector containing the polynucleotide, wherein the polynucleotide comprises a sequence encoding a truncated polycystin 1 (PC1) containing the C-terminal tail (CTT) region or a portion thereof, and the pharmaceutical composition inhibits cyst formation by localizing the CTT region or a portion thereof to the cell membrane.

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