3 0 3 8

1.25

26 1 30

30

1.25 __

30 2 20

1.25

26 1 30

1 1.25

1

Proteus vulgaris

997

Condoliase is a glycosaminoglycan lyase, which is produced in Proteus vulgaris. Condoliase is

a protein consisting of 997 amino acid residues.

C5039H7770N1360O1525S22 112,507.24

1.25 __ 2

1.25

1.25 __

1

29 1 17

1.25

26 1 30

1 1.25

1.2 mL 1.0 mL

1.25

1. ............................................................ 2 2. ........................................................................................ 3 3. .................................................................... 9 4. .......................................................... 12 5. .............................................................................. 18 6. ..... 22 7. .................................. 24 8. .............................. 49 9. 1 .................................................................................................... 49

1.25 __

2

1.

1

1

Proteus vulgaris

1985 Dr.Brown

2017 12

2014 3 GMP

1.25 __

3

8.1

/CTD 5.3.5.1-1: 6603/1021 CTD 5.3.5.1-2: 6603/1031

MRI X

Modic Pfirrmann

MRI X

1.25

1.25

2. 2.1 2.1.1

Proteus vulgaris MCB WCB

MCB WCB ICH Q5AR1ICH Q5B

ICH Q5D

WCB

2.1.2

2.1.3

MCB WCB 2.1.1

2.1.4

1.25 __

4

AB

C D/CTD 5.3.3.2-1: SKK6603J01 A

B/CTD 5.3.5.1-1: 6603/1021 CCTD 5.3.5.1-2:

6603/1031 D

A B: B C:

C D:

B

C

CTD 4.2.3.7.7-1

2.1.5

2.1.5.1 1

1

/ C N

pH

2.1.5.2

2.1.5.3 HCP DNA

HCP

2.1.6

N pH

HCPSDS-PAGE

N HCPSDS-PAGE

2.R.2

2.1.7

*

*

*

*

*

* *

mitsuya*

1.25 __

5

2

2

D 3 -60 5C 36 /

D 3 5 3C 12

25 2C 28

D 1 120 luxh

200 Wh/m2

36

/

-6024

2.2

2.2.1 1 1.25

20%

1.5 4000

2.2.2

2.2.3

1

2.2.4

pH

2.2.5 3

1.25 __

6

3

D 3 5 3C 36

D 3 25 2C 6

D 1 40 2C 6

D 1 5C 120 luxh

200 Wh/m225

2824

2.R

2.R.1

C D

C D

C D

2

1.25 __

7

2

2.R.2 HCP

HCP

HCP

ELISA

1.25 __

8

ELISA

ELISA HCP

HCP

Proteus vulgaris

HCP CBB

HCP

HCP SDS-PAGE HCP

HCP

7.R.7.2

7.R.9

HCP

SDS-PAGE ppm HCP

HCP ELISA

HCP ELISA

ELISA

ELISA

HCP ELISA

ELISA

2.R.3 4000

*

*

*

mitsuya*

1.25 __

9

3.

L4/L5 MRI

MRI /

4 CTD 4.2.1.2-1 CTD 4.2.1.2-2

4

MRI mm3 mm3 MRI

9 7852.2 680.40 - 1 10 - 16.8 1.08 - 6 111.8 28.70 79.7 20.70 1/70.2 3 127.2 42.30 96.7 13.10 1/61.7

3.1

3.1.1

3.1.1.1 CTD 4.2.1.2-1 1) 37 232 nm

A 100%

3 611.5% B 621.2%

C 821.0% D 690%

1101.5% 1%

37 TCA

280 nm

3.1.1.2 0.2125 U/mL2)162000 pkU/mL3)

374) 25 U/mL 80 pkU/mL

GAG 5)

5 U/mL 80 pkU/mL 5 U/mL

16 pkU/mL 1 U/mL 16 pkU/mL

CTD 4.2.1.1-6

1) ABCD

2) 1 U 37pH8.0 1 1 mol 3) 1 pkU 37pH6 DL--p- 1 1 pmol p- 4) 37 5) GAG

1.25 __

10

0.162.5 U/mL37 4)

0.5 U/mL107677%1316173%GAG 5) 2.5 U/mL47.833.66% 12.5 mU/mL48.66

4.47%30.716.27% 25.586.10%CTD

4.2.1.1-5

CTD

4.2.1.1-9Appl Microbiol 1975;

29: 145-51

GAG

3.1.1.3 0.2200 mU/discL3/L4L6/L7 4

7 X 7

6)7) 2 mU 76.212.75% 6.50.9 mg

92.382.70% 13.42.9 mgCTD 4.2.1.1-2

150 U/disc1000 pkU/discT13/L1L5/L6 6

148 13

100% 13 : 78.114.0%

1 U : 48.59.6% 50 U : 24.54.7%: 20.14.7%

X 8) 50 U

100% 13

: 96.21.3% 50 U : 65.34.5%: 56.09.9% CTD 4.2.1.1-

7 CTD 4.2.1.1-8

3.1.2 CTD 4.2.1.1-1

9)550 U/disc10)

7 50%24/48 59 75%36/48

6) X (BCEF)/(ABDE)

7) 8) X (acbd)/(2ab)100

9) 59 6 5

48 10) 3 1

9.7 6.8 U

1.25 __

11

3.2

5

5

CTD

SD 1 8

FOB

0.2220 U/kg

CTD 4.2.1.3-1

1 34

0.2220 U/kg CTD 4.2.1.3-3

HEK293 5/

hERG 0.04360.4364.36 mU/mL

in vitro CTD 4.2.1.3-4

1 34

0.2220 U/kg CTD 4.2.1.3-3

SD 1 6

1

0.2220 U/kg CTD 4.2.1.3-2

1 34

0.2220 U/kg CTD 4.2.1.3-3

3.R

3.R.1

. ; 2001. p43-8

GAG

CTD 5.4-53: . ; 1989. p10-22

CTD 5.4-1: Macnab 3 . ;

1999. 190-206CTD 5.4-5: 2 . ; 2011

CTD 4.2.1.1-9Appl Microbiol 1975; 29: 145-51

CTD 4.2.1.1-5

CTD 4.2.1.1-2 CTD 4.2.1.1-7 CTD 4.2.1.1-8

CTD 4.2.1.1-1

1.25 __

12

4.

: U/mL: mU/mL

ELISA : ng/mL1 ng mU125I

TCA

ELISA tmax

4.1

4.1.1

4.1.1.1 3 // 125I 100 U/kg 3 /

/ 125I 100 U/kg TCA

ELISA 6

5 332 mU/mL

CTD 4.2.2.2-44.2.2.2-5

6 125I 100 U/kg

Cmax

(mU/mL) tmax (h) t1/2 (h) AUC0-

(mUh/mL)

3 1230a)b) - 95 4075 c) d) TCA 3 1191 a)b) - 116 3059 c) d) ELISA 3 634 a) - 1.5 239.7 c) d)

3 128 1.0 - 2401 c) e) TCA 3 56 0.5 - 1402 c) e) ELISA 3 21 0.5 1.1 32.2

3 88 1.0 - 2097 c) e) TCA 3 31 1.0 - 1231 c) e) ELISA 3 7 1.0 1.6 23.6

-: a) 5 b) mUeq./mLc) mUeq.h/mL d) e) AUC0-168h

4.1.1.2

6 125I 50 U L5/L6ELISA

ELISA :

mU/mL: mU/mL 2

0.40.3 mU eq./mL 14 0.20.5 mU eq./mL AUC0-

336h 11639 mU eq.h/mL TCA

2 517% 24 247%

CTD 4.2.2.2-1

1.25 __

13

3 / 125I 25 U L5/L610100 1000 U

100 U TCA ELISA

7

CTD 4.2.2.2-14.2.2.2-24.2.2.2-3

7 125I

U

Cmax

(mU/mL) tmaxa) (h) t1/2 (h)

AUC0- (mUh/mL)

25 3 0.72 0.03 b) 168 - 79.2 0.6 c) d)

TCA 3 0.24 0.03 b) 168 - 33.7 1.9 c) d) ELISA 3 BLQ - - -

10 3 9.9 1.1b) e) - 22.4 9.0 42.3 4.6c)

TCA 3 9.7 1.1 b) e) - 25.1 7.3 18.1 3.4c) ELISA 3 4.0 1.4 e) - 1.1 0.5 3.5 0.7

100

3 76.4 1.9 b) e) - 24.4 2.3 342 12c) TCA 3 72.4 1.8 b) e) - 44.0 24.9 123 7c)

ELISA 3 29.1 2.7 e) - 1.5 0.7 22 5

3 BLQ - - -

1000

3 972.1 109.7 b) e) - 23.5 3.6 4517 996c) TCA 3 925.4 104.8 b) e) - 46.2 20.4 2310 558c)

ELISA 3 721.6 92.6 e) - 1.4 0.2 1362 630

3 746 226 e) - 1.1 0.5 1260 484

100 3 7.2 1.1 b) 8 32.2 8.6 309 44c) f)

TCA 3 4.0 2.2 b) 2 20.7 5.7 82 30c) f) ELISA 3 2.1 1.3 2 - 25.0 18.1f)

-: BLQ: ELISA : < mU/mL: < mU/mL a) b) mUeq./mL c) mUeq.h/mLd) AUC0-336h e) 5 f) AUC0-last

4.1.1.3 3 100 U/kg

ELISA AUC0- 31581392 25731511 mUh/mLt1/2 1.1

0.46 1.30.31 CTD 4.2.2.2-6

4.1.2

4.1.2.1

3 // 220 200 U/kg 1 1 28 1

15 29 1

2 U/kg U/mL20 U/kg 1

Cmax/ 235.9/409.1 U/mLtmax

1/1 AUC0-24h 157.9/299.0 Uh/mL 200 U/kg 2

Cmax 5465/5767 U/mLtmax 1/2 AUC0-24h

7850.8/5615.5 Uh/mL 15 29 11)

CTD 4.2.3.2-2

11) 28 4.2.3.2-1 220 200 U/kg/ 1556

5 / IgG 14

1.25 __

14

4.1.2.2

3 / 220 200 U/kg 1 1 29 114

28 1

8 14 200 U/kg

28 U/mL12)CTD 4.2.3.2-4

8 1 U/kg Cmax (mU/mL) tmax (h)a) t1/2 (h) AUC0-last (mUh/mL)

2 0.466 0.279 2 - 0.631 0.397 0.558 0.156 1 1.8 b) 1.86 0.85

20 5.26 0.99 0.5 4.2 2.3 20.4 4.73 5.93 1.32 1 3.7 2.1 28.2 11.2

200 114 105 2 6.4 3.5 752 252 53.6 9.2 1 5.4 0.9 463 176

3 /-: a) b) 1

4.2 4.2.1

3 / 125I 100 U/kg 5 30

5

5

373.9% 30

CTD 4.2.2.3-1

3 / 125I 100 U/kg 0.5424 168

4

168

0.05%CTD 4.2.2.3-1

3 / 125I 50 U

3 14

0.30.07% 1.00.3% 0.1%

3 14

53.47.8%: 29.823.9%: 23.616.2% 25.08.4%: 11.44.9%:

13.63.8%

86.59.0%: 46.537.8%: 40.028.9% 30.88.9%: 12.93.6%:

17.85.4%CTD 4.2.2.2-1

2 / 2 U L5/L6

371430 90

ELISA 9 CTD 4.2.2.3-3

12) 29 4.2.3.2-3 220 200 U/kg/ 1555

26 / IgG 15

1.25 __

15

9 2 U

A B A B A B

3 30.9 87.7 BLQ BLQ 30.9 87.7

ELISA 10.5 25.5 BLQ 3.3 10.5 28.9

7 BLQ BLQ BLQ BLQ - -

ELISA 3.1 2.3 1.7 6.9 4.8 9.2

14 BLQ BLQ BLQ 55.08 - 55.08

ELISA BLQ 1.5 - 26.0 - 27.5

30 BLQ BLQ BLQ BLQ - -

ELISA BLQ BLQ 7.9 BLQ - 7.9

90 BLQ BLQ BLQ BLQ - -

ELISA BLQ BLQ BLQ BLQ - - %-: BLQ: mU/mLELISA mU/mL

1 / 125I 50 U 2 3 2 4

12 24

CTD 4.2.2.3-2

2 / 2 U L5/L6

371430 90

7 1 21.7%

mU/mLELISA

10 CTD 4.2.2.2-6 10 2 U ELISA

A B A B A B 3 14.3 1.0 14.1 0.2 28.4 1.2 7 BLQ 22.9 BLQ 10.6 - 33.4 14 9.7 11.9 BLQ 1.9 9.7 13.8 30 2.3 0.2 2.0 BLQ 4.3 0.2 90 BLQ BLQ BLQ - - -

%-: BLQ: mU/mL

4.2.2

3 / 125I 100 U/kg 5 30

/ 0.730.08 0.790.07

CTD 4.2.2.3-1

1 // 125I 100 1000 U 530

2 SDS-PAGE 125I

125I

CTD 4.2.2.2-1

4.2.3 CTD 4.2.2.3-4 12 18 3 // 125I 100 U/kg

5 30 4 24 5

5

0.3%

1.25 __

16

4.3 CTD 4.2.2.2-1

3 125I 50 U L5/L6 3 14

SDS-PAGE 3

14 125I 14 125I

125I125I 125I

4.4 4.4.1

3 125I 100 U/kg 7

68.812.4% 5.60.3%12 24

TCA 8%CTD 4.2.2.2-

4

3 125I 100 U/kg 7

68.81.1% 5.62.2%

75.62.7% 4.40.8%12 24 TCA

16% 17%CTD 4.2.2.2-4

3 125I 100 U/kg

2 5.10.8%

66.76.7% 3.91.9% TCA 06

1 21%624 33%2448 82.3%CTD

4.2.2.3-1

6 125I 50 U L5/L6 14

38.49.9% 4.01.3%

TCA 3.30.7%CTD 4.2.2.2-1

3 125I 100 U 7

75.92.6% 8.51.8% TCA

5.30.3%CTD 4.2.2.2-1

3 125I 100 U 7

85.28.7% 14.74.5% TCA

5.40.5%CTD 4.2.2.2-1

4.4.2 CTD 4.2.2.3-4 12 18 125I 100 U/kg

TCA AUC0-24h 7.8 7.5

11

125I

1.25 __

17

4.R 4.R.1

125I 50 U

ELISA

CTD 4.2.2.2-1

125I 50 U

24 CTD 4.2.2.3-2

125I 50 U 14

CTD 4.2.2.2-1

6.2

570 0.050.2

Acta Biomater 2015; 26: 215-24Curr Rheumatol Rev 2009; 5: 1-18

; 23: 1-15, 1980

1.25 __

18

13)Arginin-C-ProteaseCasepase-1

Proline-endopeptidase

5.

in vivo

5.1

5.1.1 CTD 4.2.3.1-74.2.3.1-84.2.3.1-9

Swiss 5 / 0 2000 U/kg

5.1.2 CTD 4.2.3.1-104.2.3.1-114.2.3.1-12

4.2.3.1-13 Wistar 5 / 0 2000 U/kg

5.1.3 5.1.3.1 26 CTD 4.2.3.1-5

9 / 00.251416 50 U

X 0.25 U

16 U 16 U

1 U

4 U

16 U

5.1.3.2 3 CTD 4.2.3.1-6 18 / 0 50 U

X

13) http://web.expasy.org/peptide_cutter/

1.25 __

19

5.1.3.3 CTD 4.2.3.1-144.2.3.1-154.2.3.1-164.2.3.1-17

2 / 0 2000 U/kg

5.1.4 5.1.4.1 13 CTD 4.2.3.1-1

9 / 00.25 10 U

X 0.25 U

0.25 U

0.25 U

0.25 U

5.1.4.2 26 CTD 4.2.3.1-24.2.3.1-3 4 / 00.251.6 10 U

X 0.25 U

0.25 U

0.25 U

5.2

5.2.1 28 CTD 4.2.3.2-14.2.3.2-2

Wistar 10 / 0220 200 U/kg/ 1 1 28

2 U/kg/28

200 U/kg/

5.2.2 29 CTD 4.2.3.2-34.2.3.2-4

4 / 0220200 U/kg/ 1 1 29

200 U/kg/

5.3 in vitro CTD 4.2.3.3.1-1

CTD 4.2.3.3.1-2in vivo

CTD 4.2.3.3.2-1

1.25 __

20

5.4

7.R.7.2 ICH S1A

5.5

5.5.1

5.5.1.1 CTD 4.2.3.5.1-1

SD 22 / 0220 200 U/kg/ 4

2 7 1 1

200 U/kg/

200 U/kg/ 2 U/kg/

5.5.1.2 CTD 4.2.3.5.1-2

Wistar 20 / 0 200 U/kg/ 7

7 7 1 1

200 U/kg/

5.5.2

5.5.2.1 CTD 4.2.3.5.2-1 Wistar52 / 0220 200 U/kg/ 716 1 1

200 U/kg/

5.5.2.2 CTD 4.2.3.5.2-2

Wistar20 / 0 200 U/kg/ 1217 1 1

200 U/kg/

5.5.2.3 CTD 4.2.3.5.2-3

New Zealand White16 / 0220 200 U/kg/ 618

1 1 200 U/kg/

200 U/kg/

200 U/kg/

5.5.3 CTD 4.2.3.5.3-1 Wistar22 / 0 200 U/kg/ 15 20

1 1

1.25 __

21

F1

200 U/kg/

5.6

5.6.1 CTD 4.2.3.6-6 6 / 07.5 U/mL 10 L

5.6.2 CTD 4.2.3.6-7

6 / 07.5 U/mL 1 mL

2 1 7 1

3

5.6.3 CTD 4.2.3.6-8 36 / 07.5 U/mL0.75 v/v%1 mL

5.6.4 CTD 4.2.3.6-9

Hartley 6 / 0.548 U/mL 0.1 mL

5.6.5 CTD 4.2.3.6-10

Hartley 6 / 0.050.10.58 U/mL 0.1 mL

0.030.30.61.22.4 U/mL 0.03 mL

5.7 5.7.1

CTD 4.2.3.7.1-1

CTD 4.2.3.7.1-2CTD 4.2.3.7.1-3

5.7.2 0.03%14)

5.7.2.1 CTD 4.2.3.7.6-1 Wistar 5 / 0 6 mg/kg

5.7.2.2 CTD 4.2.3.7.6-2

14) 1000 U mg mg

*

*

*

mitsuya*

1.25 __

22

Wistar 10 / 00.040.15 0.6 mg/kg/ 28

0.6 mg/kg/

5.7.2.3

CTD 4.2.3.7.6-3

CHL/IU CTD 4.2.3.7.6-4

5.7.3 CTD 4.2.3.7.6-54.2.3.7.6-6

6 /15) 2U

5.R

6. 6.1

: U/mL

: ng/mL :

ng/mL IgE IgG

ELISA

6.2

/CTD 5.3.3.2-1 CTD

5.3.3.2-2: SKK6603J01 /CTD 5.3.5.1-1CTD 5.3.5.2-3CTD 5.3.5.2-4 CTD 5.3.3.2-

5: 6603/1021 CTD 5.3.5.1-2: 6603/1031

6.2.1

18 0.5

2.5 10 U

Cmax tmax 0.5 U 22001910 ng/mL

7 2.5 U 891903 ng/mL 14 10 U 40705690 ng/mL 14

11

IgE IgG 16)CTD 5.3.3.2-1

CTD 5.3.3.2-2: SKK6603J01

15) 2 3 16 16) IgE IgG IU/mL g/mL

*

*

mitsuya*

1.25 __

23

11

(U)

Cmax (ng/mL) tmaxa) (day) AUC0-last

(ngday/mL) 0.5 6 124 74.7 1.50 352 3280 2.5 6 858 1010 2.00 14100 19600 10 6 274 195 10.5 8850 10300

a)

147 194

1.252.5 5.0 U

12 IgG 1.25 U

2.5 U 5.0 U 2.1%1/47 4.1%2/49 12.2%6/49 26.5%

13/49 2.5 U 1 5.0 U 1

13 17) IgE

Cmax AUC0-last

13

-0.263-0.399

13 24 VAS

CTD 5.3.5.1-1CTD 5.3.3.2-3CTD 5.3.3.2-4CTD 5.3.3.2-5: 6603/1021

12

Cmax (ng/mL) tmax a) (day) AUC0-last (ngday/mL) 47 58.1 51.7 6.91 506 4127 b)

1.25 U 49 166 99.7 1.92 2750 4292 c) 2.5 U 49 201 102 1.88 3666 4256 d) 5 U 49 273 164 1.88 5778 7484 c)

a) b) 42 c) 44 d) 47

163 1.25 U

IgG 2.5%

2/81 1.2%1/82 1 52 1

13 26 18) IgE

CTD 5.3.5.1-2: 6603/1031

6.R

17)

18)

1.25 __

24

7. 13

/CTD 5.3.3.2-1: SKK6603J01 /CTD 5.3.5.1-1: 6603/1021

CTD 5.3.5.1-2: 6603/1031

/ CTD 5.3.5.4-2: SKK0197

CTD 5.3.5.4-1: 6603/1121

CTD 5.3.5.4-3: SKK6003J02

13

CTD

SKK6603J01 5.3.3.2-1 /

18 0.52.510 U 40 U

/

6603/1021 5.3.5.1-1 /

195a) 1.252.5 5 U

/

6603/1031 5.3.5.1-2

166a) 1.25 U/mL

a)

7.1 /CTD 5.3.3.2-1: SKK6603J01

19) 24 : 6

/

/6.2

0.52.510 40 U 10 U

2/6 X

40 U

18 0.52.5 10 U 6

20) 0.5 U 6 12

0.5 U 1

12 1 VAS

mm2.5 U 4 -61.528.310 U 3 -5.059.0

21)

18

0.5 U 2 1

0.5 U 50%3/6

19) 2050 2

6 3 NSAIDs

MRI L4/L5 L5/S1 SLR 70

20)

21)

1.25 __

25

2.5 U 66.7%4/6 10 U 100%6/6 2

4 5 1 1 0 X 0 0 2

MRI

10 U 2

0.5 2.5 U 10 U

2.5 10 U

7.2 /CTD 5.3.5.1-1: 6603/1021 2008 2 2010 8 122) 184 :

46

/

6.2

1.252.5 5 U

52

195 47 1.25 U 49 2.5 U 50 5 U 49

2.5 U 1 194 47 49 49 49

1.25 U 1

193 47 48 49 49 FAS

13 18 6 5 2 5 13 29 9 5 8 7

13 : 3 3 2 2 13 : 4 5 6 6

FAS 13 24 VAS

23) 14 1.25 U 5 U

p = 0.0261 0.0132VAS

24)

22) 2070 2

6 6 NSAIDs 3

MRI L4/L5 L5/S1 L6 L5 S1

SLR 70 7 24

24 NSAIDs 3 VAS 50 mm VAS 25 mm

23) VAS 24 /

7 VAS

24) Dunnett p

1.25 __

26

14 13 24 VASFASLOCF

24 VAS a,b)

b) 13 95% p c)

47 73.2 12.0 41.9 30.9 -31.7 4.3 1.25 U 48 70.7 14.4 23.3 26.6 -46.7 3.9 -14.9 [-28.4, -1.4] 0.0261 2.5 U 49 67.4 12.3 26.8 29.5 -41.1 4.2 -9.3 [-22.7, 4.0] 0.2337 5 U 49 70.5 12.4 23.4 27.0 -47.6 4.0 -15.9 [-29.0, -2.7] 0.0132

mm a) mm b) VAS c) Dunnett p

25) 74.5%35/47 1.25 U 77.6%38/49

2.5 U 83.7%41/49 5 U 85.7%42/49

13 2 1

1.25 U 1 2.5 U 2 1 13

1 1.25 U 1 2.5 U 1

14.9%

7/47 1.25 U 46.9%23/49 2.5 U 44.9%22/49 5 U 61.2%30/49

2 13 8 10 2 2 3 4

0 12 10 13 X 0 4 4 8

1 0 1 3

1.25 U 5 U

7.3 CTD 5.3.5.1-2: 6603/1031 2012 3 2014 2 126) 160 :

80

1.25 U 52

25) 13 / 13

30%MedDRA PT X 3 mm MedDRA PT X 5MedDRA PT X Modic Type 13 MedDRA PT VAS

MedDRA PT MedDRA PT MedDRA PT

26) 2070 2 6 6 NSAIDs

3 MRI L4/L5 L5/S1

L6 L5 S1

SLR 70 7 24

24 3 VAS 50 mm VAS 25 mm

1.25 __

27

166 82 84

3 163 81 82 FAS

13 17 11 6 13 27 13 14

13 : 3 4 13 : 8 7

13 : 3 1 13 : 2 1

FAS 13 24 VAS

27) 15

p = 0.0011VAS180 180

15 13 24 VASFASLOCF

24 VAS a,b)

b) 13 95% p

81 74.6 12.5 39.2 31.0 -34.3 3.3 -15.2 [-24.2, -6.2] 0.0011

82 72.4 12.3 22.9 28.0 -49.5 3.3 mm a) mm b) VAS180 180

25) 79.0%64/81 90.2%74/82

6

3 1 4

1 1

33.3%

27/81 57.3%47/82 10

20 4 20 X 3 19 6 2

1.25 U

7.R 7.R.1

/CTD 5.3.5.1-1: 6603/1021

/CTD 5.3.3.2-1: SKK6603J01 12 1

2.5 10 U 10 U

2/6 X

2.5 U 6603/1021 27) VAS /

VAS 24 7 VAS

1.25 __

28

2.5 U

2.5 U 1.25 U 5 U

6603/1021 2.5 U

6603/1021 13 24 VAS

1.25 U 5 U

2.5 U

146603/1021

24 VAS 69.1 mmFAS

40.4%19/47 1.25 U 47.9%23/48 2.5 U 61.2%30/49

5 U 49.0%24/49 1 17.0%8/47 1.25 U

18.8%9/48 2.5 U 22.4%11/49 5 U 10.2%5/49 MRI

12.8%6/47 1.25 U 14.6%7/48 2.5 U 18.4%

9/49 5 U 4.1%2/49 2.5 U

. ; 2005

6603/1021 1.25 U 5 U

14

19 1.25 U

6603/1031 1.25 U

1.25 U

7.R.2 7.R.2.1

/CTD 5.3.5.1-1: 6603/1021 CTD 5.3.5.1-2: 6603/1031

24 VAS

2 . ; 2011. p19-20 QOL

FDA

28)QOL

28) Guidance Document for the Preparation of IDEs for Spinal Systems. U.S. Department of Health and Human Services Food and Drug Administration

Center for Devices and Radiological Health, Orthopedic Devices Branch Dvision of General and Restorative Devices Office of Device Evaluation; 2000

1.25 __

29

/CTD 5.3.3.2-1:

SKK6603J01 1 VAS 1 VAS

24 VAS

6603/1021 6603/1031

13

. ; 2011. p525-32

2 2007; 18: 513

13

13 24

VAS

7.R.2.2 6603/1131 29)ITT

13 24 VAS1.25 U

6603/1131 ITT 13 24

VAS 16

p = 0.6212

MMRM

unstructured

16 13 24 ITTMMRM

24 VAS a,b)

b) 13 95% p

94 76.7 12.7 36.4 29.7 -39.6 3.4 1.9 [-5.6, 9.4] 0.6212

280 74.4 14.0 36.6 32.8 -37.7 2.1 mm a) mm b) MMRMunstructured

6603/1131

6603/1131

29)

30-70 90 1.25 U270 104 13 24

1.25 __

30

MRI 17

2%6603/1131 20%

6603/1131 6603/1031

7.R.2.3

6603/1131

17

356 374

63 (17.7) 215 (57.5)

286 (80.3) 81 (21.7) 7 (2.0) 78 (20.9)

311 (87.4) 100 (26.7) 45 (12.6) 274 (73.3)

%

6603/1131

6603/1031

6603/1131

6603/1131

6603/1021 6603/1031 1.25 U

6603/1131

MRI

7.R.2.3

6603/1031 FAS 13 24 VAS

18

6603/1021 1.25 U 6 5 U 13 8

95% 14.025.0, 52.9 6.623.5, 36.66603/1131 3.66.1,

13.3

1.25 __

31

18 13 24 VASFASLOCF

a) 1.25 U

2029 -28.4 26.1 (21) -43.3 26.3 (14) -15.2 [-33.9, 3.5] 3049 -37.1 33.9 (44) -49.9 28.5 (52) -16.2 [-29.0, -3.5] 50 -40.2 28.6 (16) -53.6 28.9 (16) -13.0 [-34.8, 8.9]

-28.0 28.8 (48) -44.3 30.6 (51) -17.0 [-28.8, -5.2] -46.2 31.4 (33) -58.1 21.1 (31) -13.4 [-26.8, 0.0]

BMI 22.9 -33.1 31.2 (41) -48.5 29.3 (40) -15.0 [-28.5, -1.5] 22.9 -37.8 31.0 (40) -50.5 27.2 (42) -15.4 [-28.4, -2.5]

L4/5 -35.2 34.3 (37) -51.6 27.3 (45) -18.2 [-31.0, -5.4]

L5/S1 -32.7 27.7 (40) -46.2 29.2 (36) -14.0 [-27.2, -0.8] L5/L6 -65.1 15.0 (4) -72 (1) -5.5 [-112.6, 101.5]

-37.2 45.1 (12) -26.6 34.7 (9) 3.9 [-32.2, 40.0]

-34.9 28.4 (68) -53.4 25.4 (71) -19.0 [-28.0, -10.0]

b) 136 -39.1 30.4 (42) -50.6 26.2 (39) -11.4 [-23.9, 1.2] 136 -31.5 31.6 (39) -48.5 30.0 (43) -20.0 [-33.4, -6.6]

24 b)

74.1 -29.1 27.3 (39) -43.1 24.6 (42) -15.8 [-27.5, -4.2] 74.1 -41.4 33.4 (42) -56.3 30.1 (40) -16.1 [-30.4, -1.8]

MRI

-37.5 29.7 (70) -50.1 27.9 (74) -13.6 [-23.1, -4.2] -22.7 37.3 (11) -44.1 31.2 (8) -25.4 [-58.7, 8.0]

-38.7 31.0 (26) -53.2 28.0 (31) -17.5 [-32.9, -2.1] -33.9 31.2 (55) -47.3 28.2 (51) -13.9 [-25.3, -2.5]

mm a) VAS180 180

b)

6603/1021

MRI

Radiology 2004; 231: 352-8Spine 2008; 33: 273-9

6603/1021

1.25 U 6 5 U 7 13

24 VAS11

95% 2.431.7, 36.6 4.528.0, 37.0

1.25 U 7 5 U 9 5

7.949.8, 65.73.852.1, 44.5

6603/1031

1.25 __

32

7.R.3

7.R.3.1

3.R.1

30) MRI X 31) 19

13 52 30%

5

3 mm 32)

19 MRI X 13 52

30%

0 0 1.25 U 8/120 (6.7) 10/101 (9.9) 2.5 U 4/47 (8.5) 5/39 (12.8) 5 U 6/44 (13.6) 9/37 (24.3)

5

6/128 (4.7) 2/112 (1.8) 6/89 (6.7) 1.25 U 8/131 (6.1) 3/120 (2.5) 7/101 (6.9) 2.5 U 3/49 (6.1) 3/47 (6.4) 1/39 (2.6) 5 U 6/49 (12.2) 7/44 (15.9) 4/37 (10.8)

3 mm

0 3/112 (2.7) 0 1.25 U 0 0 0 2.5 U 0 0 0 5 U 1/49 (2.0) 1/44 (2.3) 0

Modic Type 13

4/112 (3.6) 15/89 (16.9) 1.25 U 21/120 (17.5) 28/101 (27.7) 2.5 U 13/47 (27.7) 14/39 (35.9) 5 U 12/44 (27.3) 11/37 (29.7)

/%

Modic 33)

30%

Spine 1996; 21: 1556-64J Neurosurg Spine 2010; 13: 562-7.

30) /CTD 5.3.5.1-1: 6603/1021 CTD 5.3.5.1-2: 6603/1031 31) 1. /CTD 5.3.5.1-1: 6603/1021

CTD 5.3.5.1-2: 6603/1031 MRI

32) FDA 28) 33) MRI Type 0 Type 1 T1 T2

Type 2 T1 T2 Type 3 T1 T2

1.25 __

33

4060 J Clin Invest 1996; 98:

996-1003 10

Spine 2002; 27: 2631-4410 1130

30 30

50 Spine 2006; 31: 1522-31

10 10

20 2040

40 Surg Radiol Anat 2000; 22: 13-9

20

20

-

CTD 4.2.3.1-135.1

Spine 1982; 7: 97-102

10

100 U

1000 CTD 4.2.3.1-4

1.25 __

34

Spine 2007; 32: 1816-25

20 70 21 2029

5070

21

2029 3049 5070

37 41 69 145 22 43 28 (75.7) 37 (90.2) 58 (84.1) 122 (84.1) 13 (59.1) 36 (83.7) 0 1 (2.4) 7 (10.1) 4 (2.8) 1 (4.5) 2 (4.7) 0 0 4 (5.8) 0 2 (9.1) 0 0 2 (4.9) 5 (7.2) 12 (8.3) 2 (9.1) 2 (4.7) 16 (43.2) 17 (41.5) 23 (33.3) 47 (32.4) 3 (13.6) 11 (25.6) 5 (13.5) 4 (9.8) 9 (13.0) 21 (14.5) 0 9 (20.9) 1 (2.7) 6 (14.6) 12 (17.4) 47 (32.4) 3 (13.6) 9 (20.9) 13 (35.1) 6 (14.6) 19 (27.5) 30 (20.7) 3 (13.6) 5 (11.6) X 6 (16.2) 15 (36.6) 4 (5.8) 29 (20.0) 0 5 (11.6) 0 0 0 0 0 3 (7.0) 3 (8.1) 5 (12.2) 6 (8.7) 14 (9.7) 1 (4.5) 1 (2.3) 3 (8.1) 4 (9.8) 2 (2.9) 2 (1.4) 0 1 (2.3) 2 (5.4) 3 (7.3) 6 (8.7) 6 (4.1) 0 1 (2.3) 2 (5.4) 1 (2.4) 3 (4.3) 3 (2.1) 2 (9.1) 2 (4.7) 2 (5.4) 0 4 (5.8) 2 (1.4) 2 (9.1) 0 0 0 0 0 2 (9.1) 0 1 (2.7) 0 6 (8.7) 3 (2.1) 0 2 (4.7) 2 (5.4) 0 3 (4.3) 2 (1.4) 0 1 (2.3)

0 11 (26.8) 1 (1.4) 20 (13.8) 0 5 (11.6) 5 (13.5) 8 (19.5) 2 (2.9) 12 (8.3) 0 0 2 (5.4) 1 (2.4) 1 (1.4) 1 (0.7) 0 0 1 (2.7) 6 (14.6) 12 (17.4) 46 (31.7) 3 (13.6) 9 (20.9)

%

2070

2070

70

1.25 __

35

7.R.3.2

Spine 1984; 9: 479-85

30)34) 22

3 1 1.25 U

1

22

1.25 U 2.5 U 5 U 128 131 49 49 44 (34.4) 31 (23.7) 7 (14.3) 9 (18.4) 35 (27.3) 26 (19.8) 6 (12.2) 9 (18.4) 0 3 (2.3) 0 0 8 (6.3) 2 (1.5) 0 0 1 (0.8) 1 (0.8) 0 0 2 (1.6) 0 1 (2.0) 1 (2.0) 1 (0.8) 0 0 0 1 (0.8) 0 0 0

%

35) 23

1 10.9%14/128 18.8%43/229

23

1.25 U 2.5 U 5 U 128 131 49 49 48 (37.5) 49 (37.4) 13 (26.5) 14 (28.6) 42 (32.8) 48 (36.6) 13 (26.5) 14 (28.6) 8 (6.3) 2 (1.5) 0 0 1 (0.8) 1 (0.8) 0 0

% 34) MedDRA PT 35) MedDRA PT

1.25 __

36

7.R.3.3

J Allergy Clin Immunol 1985; 75: 659-62

Proteus vulgaris

Proteus vulgaris

30)36) 24

1.25 U 1

24

1.25 U 2.5 U 5 U 128 131 49 49 6 (4.7) 11 (8.4) 4 (8.2) 3 (6.1) 1 (0.8) 3 (2.3) 2 (4.1) 2 (4.1) 0 2 (1.5) 0 0 1 (0.8) 2 (1.5) 0 1 (2.0) 0 2 (1.5) 0 0 0 2 (1.5) 0 0 0 1 (0.8) 0 0 0 1 (0.8) 0 0 0 1 (0.8) 0 0 0 1 (0.8) 0 0 0 0 1 (2.0) 0 2 (1.6) 0 1 (2.0) 0 1 (0.8) 0 0 0 1 (0.8) 0 0 0

%

IgE

36) MedDRA SMQ

1.25 __

37

IgG /CTD 5.3.5.1-1: 6603/1021 2.1%1/47

1.25 U 4.1%2/49 2.5 U 12.2%6/49 5 U 26.5%13/49

CTD 5.3.5.1-2: 6603/1031 2.5%2/81 1.2%1/82

6603/1021 2.5 U 5 U 6603/1031

1

Proteus vulgaris

6603/1031 1

52

6603/1021

37)

7.R.9

37) http://www.mhlw.go.jp/houdou/2004/10/h1028-2a.html

1.25 __

38

7.R.9

7.R.3.4

30)38) 25

6603/1021 1 6603/1031

1 1.25 U 1

25 a) 128 229 16 (6.4) 22 (9.6) 1 (0.8) 1 (0.4) 1 (0.8) 0 2 (1.6) 0 1 (0.8) 0 1 (0.8) 0 1 (0.8) 0 9 (7.0) 20 (8.7) 1 (0.8) 1 (0.4)

% a) 6603/1021 6603/1031 1.25 U 2.5 U 5 U

6603/1031

38) 1 MedDRA PT

1.25 __

39

7.R.9

7.R.4

6603/1021 2.5 U 5 U 6603/1031

1 IgG 6603/1031 1

26

IgG

39) 24 VAS

36)

7.R.7.2

7.R.5

30) 26

CTD 5.3.5.4-5

39) / 2.5 U 13 5 U 13 13 26

1.25 __

40

26

6603/1021 6603/1031 FAS

356

231 6603/1021 103 6603/1031 128 6603/1021 6603/1031 50.3%179/356 6603/1021

: 73/193 6603/1031 : 106/163

X MRI

ODI

13.3%17/128 7.9%18/228

1 1

6 1

7.4%5/68 6.5%7/108

2.9%2/68 0.9%1/108 ODI40)

-24.715.0%-32.718.6%

Spine 2013; 38: E1051-7 24 5 MRI

4

1 1993; 4: 145

7.R.6

7.R.6.1

CTD 5.3.5.1-2: 6603/1031 13 24

VAS

40)

10 6

1.25 __

41

6603/1031 FAS 13 MRI

24 VASODI40) SLR 41)

27ODI

SLR

27 6603/1031 FASLOCF

a,b)

b) 13 95%

mm3 81 1300.7 559.9 1098.6 453.8 -190.7 23.4

-98.3 [-162.3, -34.4] 82 1243.5 552.5 961.2 416.4 -289.1 23.1

24 VASmm

81 52.4 30.6 30.2 29.1 -21.4 2.9 -7.1 [-15.0, 0.8]

82 50.2 27.1 22.2 26.3 -28.5 2.9

ODI 81 40.5 13.6 26.0 18.3 -13.4 1.9

-5.6 [-10.7, -0.4] 82 38.0 12.9 19.7 15.7 -18.9 1.9

SLR %

81 0 46 (56.8) c)

82 0 65 (79.3) c) a) b) 180 180 c)

7.R.6.2

1 30)

MB Orthop 2003; 16: 30-4

6603/1131

MRI

7.R.6.3

30)6

41) 70

1.25 __

42

11 . ;

2011

90% 1

2001; 36: 487-90 2003; 13: 959-64

6

7.R.6.4

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L4/L5 L5/S1

2 . ; 2011L4/L5 L5/S1

5%L4/5 L5/S1

L4/L5 L5/S1 J Korean Neurosurg Soc

2013; 54: 379-83J Spinal Disord 1993; 6: 351-9 L4/L5 L5/S1

L4/L5

L5/S1

42)

L4/L5 L1/L2

L4/L5 70% 1030%

42) J Korean Neurosurg Soc 2013; 54: 379-83J Spinal Disord 1993; 6: 351-9J Korean Neurosurg Soc 2010; 48: 119-24Neurol Med Chir 2011;

51: 423-6Clin Orthop Relat Res 1991; 269: 151-6

1.25 __

43

Neuroradiography 2000; 42: 451-5

0.41.0 U

1.25 U 1.64.0

1 55.2%Spine 2007; 32: 328-33

L1/L2 1.25 U

L4/L5 L5/S1

1.0 mL . ;

2001L4/5 L5/S1 1.0 mL

6603/1031 13 24 VAS

ODISLR

7.R.3.1

7.R.2.3

L4/L5 L5/S1

1.25 __

44

7.R.7

7.R.7.1

CTD 5.3.5.1-2: 6603/1031 7.R.1

1 1 1.25 U

L4/L5 L5/S1 L4/L5

L5/S1 1.25 U 7.R.6.4

1 1 1.25 U

7.R.7.2

30)

39

1 52 1

CTD 5.3.5.4-5

7.R.5

2 16%

52 77%J Spinal Disord 1998; 11: 253-60

1.25 __

45

2 15

70% 51/57 21/27 24/33

43)

43)

7.R.3.1

IgE IgG J Allergy Clin Immunol 1985; 75: 659-62

IgG 3/229

7.R.4 2 13 52

52

52

IgE IgG

43) Clin Orthop Relat Res 1999; 363: 121-5Spine 1987; 12: 800-2Clin Orthop 1986; 206: 45-9

1.25 __

46

7.R.7.3

19851994 486

2 77 16%

17 3.5%NEW MOOK 2. .

; 1997. p266-74

1

7.R.3.3

134 10 268

J Neurosurg 1986; 65: 1-8

5 U /CTD 5.3.5.1-1: 6603/1021 IgG

7.R.3.3

IgE

2

1.25 __

47

7.R.8

3

11 . ; 201125

2 . ; 2011

2009; 83: 1022-7 1982

Spine

1984; 9: 479-85

X

7.R.9

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48

2009

2009

7.R.3.3

7.R.10

3000

1.25 __

49

8. 8.1

CTD 3.2

/

CTD 5.3.5.1-1: 6603/1021 CTD 5.3.5.1-2: 6603/1031 MRI

MRI

8.2 GCP CTD 5.3.5.1-1CTD 5.3.5.1-2 GCP

GCP

X

9. 1

1.25 __

50

2

30 2 19

1.25

26 1 30

1.

20 12 25 20 8

1

1.1 6603/1131 ITT 13 24

VAS1.25 U

CTD 5.3.5.1-1:

6603/1021 CTD 5.3.5.1-2: 6603/1031 1.25 U

6603/1131

17.R.2.2

MRI

17.R.2.2

6603/1131 6603/1131

6603/1131

17.R.2.2

1.25 __

51

19.3%72/374

6603/1021 1.25 U 5 U 2.5 U

13 24

VAS

FAS 13 MRI 13 24

VAS

6603/1021 FAS 13 MRI

24 VASODI40) SLR 41)

28

ODISLR 6603/1031

27

28 6603/1021 FASLOCF

a,b) b)

13 95%

mm3

46 1400.1 517.1 1230.5 511.7 -166.8 30.9 1.25 U 48 1477.6 520.3 1212.8 499.4 -248.8 30.4 -82.0 [-184.6, 20.6] 2.5 U 49 1216.8 420.5 1006.8 370.4 -238.3 30.4 -71.5 [-174.4, 31.3] 5 U 49 1441.8 521.5 1188.5 457.7 -243.4 30.0 -76.7 [-178.7, 25.4]

24 VASmm

47 60.7 26.7 35.7 29.2 -21.1 3.6 1.25 U 48 53.1 27.5 22.3 26.0 -31.4 3.5 -10.3 [-22.2, 1.6] 2.5 U 49 44.9 27.8 24.6 24.5 -25.8 3.5 -4.7 [-16.7, 7.4] 5 U 49 58.4 23.1 25.4 26.7 -30.6 3.5 -9.4 [-21.2, 2.4]

ODI

47 39.0 14.3 24.1 16.2 -16.2 2.1 1.25 U 48 41.5 15.5 18.3 14.0 -20.6 2.2 -4.4 [-11.4, 2.6] 2.5 U 49 36.4 13.0 19.4 14.3 -19.8 2.1 -3.6 [-10.4, 3.2] 5 U 49 40.4 16.7 18.2 13.0 -22.0 2.1 -5.8 [-12.5, 1.0]

SLR %

47 0 25 (53.2) c)

1.25 U 48 0 40 (83.3) c) 2.5 U 49 0 31 (63.3) c) 5 U 49 0 39 (79.6) c)

a) b) 180 180 c)

1.2

1.2.1

1.25 __

52

229

6603/1131 280 29)6603/1132 991 44)

45) 36)

6603/1131

6603/1132

17.R.3.3

17.R.9

1.2.2

Spine 1984; 9: 479-85

CTD 4.2.3.6-4 10 U

40 U100 USpine 1991; 16:

43-5Spine 1996 ;21: 1952-6.

3671%

46) 80.3%286/356

44) 1.25 U 1,000 26 45) MedDRA SMQ PT46) 1995; 38: 1513-5 2003; 16: 929-37Pain Research 1990; 5 :93-8

1.25 __

53

6603/1131

6603/1132 47)

1133%46)

1.3

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1.4

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1.5 17.R.9

5

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47) MedDRA HLT

1.25 __

54

29

48)

1

1.6 1 7.R.10

29

30

1 7.R.10

29

48) 2

1.25 __

55

30

31

32

31 3

3,000

32

9

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9 15 CTD 4.2.1.2-1) CTD 4.2.1.1-9) 13 7

U: 1000AUC0- ELISA : 1362630 : 1260484

U: 1000AUC0- ELISA : 1362484 : 1260630

13 1314 115 29 114 28 13 19 15 29 14 28 14 23 114 28 115 29 14 4 14 15 14 5 28 29 15 1718 530 2 530 2 22 20

1.25 __

56

3.

8

1.25

1.25 __

i

AUC Area Under Concentration-time Curve - CBB Coomassie Brilliant Blue Cmax Maximum Concentration CTD Common Technical Document DNA Deoxyribonucleic Acid ELISA Enzyme-linked Immunosorbent Assay FAS Full Analysis Set FDA Food and Drug Administration FOB Functional Observation Battery GAG Glycosaminoglycan HCP host cell protein HEK293 5

hERG Human Ether-a-go-go Related Gene ether-a-go-go ICH Q5AR1

12 2 22 329

ICH Q5B

DNA

10 1 6 3

ICH Q5D

12 7 14 873

ICH S1A

9 4 14 315

IgE Immunoglobulin E E IgG Immunoglobulin G G ITT Intention-to-Treat LOCF Last Observation Carried Forward MCB Master Cell Bank MedDRA Medical Dictionary for Regulatory Activities ICH MMRM Mixed-effects Model Repeated Measures MRI Magnetic Resonanse Imaging NSAIDs Non-steroidal Anti-inflammatory Drugs ODI Oswestry Disability Index PT Preferred Term QOL Quality of Life SD Sprague Dawley

1.25 __

ii

SDS-PAGE SDS-Polyacrylamide Gel Electrophoresis -

SLR Straight Leg Raising SMQ Standerdized MedDRA Query MedDRA TCA Trichloroacetic acid

tmax Time to Reach Maximum Concentration VAS Visual analog scale WCB Working Cell Bank 1.25