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16 11 5 25mg 14 11 18 1 25mg 1 150,000 934 1 2 : 1-235-tumor necrosis factor receptor (human) fusion protein with 236-467-immunoglobulin G1 (human γ1-chain Fc fragment), dimmer : : 1 235 236 467 G 1 γ1 Fc 467 C 2224 H 3472 N 618 O 701 S 36 51,237.42 cdna 150,000 C : Glycoprotein (molecular weight: ca. 150,000) consisting of two subunits produced in Chinese hamster ovary cells by expression of a cdna that codes 467 amino acid residues, 1 to 235 derived from extracellular domain of human tumor necrosis factor type II receptor and 236 to 467 derived from Fc fragment of γ 1 chain of human immunoglobulin G 1 (C 2224 H 3472 N 618 O 701 S 36 ; molecular weight: 51,237.42), the major component is cleaved at C-terminal Lys 1

1 1 Leu-Pro-Ala-Gln-Val-Ala-Phe-Thr-Pro-Tyr-Ala-Pro-Glu-Pro-Gly-Ser-Thr-Cys-Arg-Leu- 21 Arg-Glu-Tyr-Tyr-Asp-Gln-Thr-Ala-Gln-Met-Cys-Cys-Ser-Lys-Cys-Ser-Pro-Gly-Gln-His- 41 Ala-Lys-Val-Phe-Cys-Thr-Lys-Thr-Ser-Asp-Thr-Val-Cys-Asp-Ser-Cys-Glu-Asp-Ser-Thr- 61 Tyr-Thr-Gln-Leu-Trp-Asn-Trp-Val-Pro-Glu-Cys-Leu-Ser-Cys-Gly-Ser-Arg-Cys-Ser-Ser- 81 Asp-Gln-Val-Glu-Thr-Gln-Ala-Cys-Thr-Arg-Glu-Gln-Asn-Arg-Ile-Cys-Thr-Cys-Arg-Pro- 101 Gly-Trp-Tyr-Cys-Ala-Leu-Ser-Lys-Gln-Glu-Gly-Cys-Arg-Leu-Cys-Ala-Pro-Leu-Arg-Lys 121 Cys-Arg-Pro-Gly-Phe-Gly-Val-Ala-Arg-Pro-Gly-Thr-Glu-Thr-Ser-Asp-Val-Val-Cys-Lys- 141 Pro-Cys-Ala-Pro-Gly-Thr-Phe-Ser-Asn-Thr-Thr-Ser-Ser-Thr-Asp-Ile-Cys-Arg-Pro-His- 161 Gln-Ile-Cys-Asn-Val-Val-Ala-Ile-Pro-Gly-Asn-Ala-Ser-Met-Asp-Ala-Val-Cys-Thr-Ser- 181 Thr-Ser-Pro-Thr-Arg-Ser-Met-Ala-Pro-Gly-Ala-Val-His-Leu-Pro-Gln-Pro-Val-Ser-Thr- 201 Arg-Ser-Gln-His-Thr-Gln-Pro-Thr-Pro-Glu-Pro-Ser-Thr-Ala-Pro-Ser-Thr-Ser-Phe-Leu- 221 Leu-Pro-Met-Gly-Pro-Ser-Pro-Pro-Ala-Glu-Gly-Ser-Thr-Gly-Asp-Glu-Pro-Lys-Ser-Cys- 241 Asp-Lys-Thr-His-Thr-Cys-Pro-Pro-Cys-Pro-Ala-Pro-Glu-Leu-Leu-Gly-Gly-Pro-Ser-Val- 261 Phe-Leu-Phe-Pro-Pro-Lys-Pro-Lys-Asp-Thr-Leu-Met-Ile-Ser-Arg-Thr-Pro-Glu-Val-Thr- 281 Cys-Val-Val-Val-Asp-Val-Ser-His-Glu-Asp-Pro-Glu-Val-Lys-Phe-Asn-Trp-Tyr-Val-Asp- 301 Gly-Val-Glu-Val-His-Asn-Ala-Lys-Thr-Lys-Pro-Arg-Glu-Glu-Gln-Tyr-Asn-Ser-Thr-Tyr- 321 Arg-Val-Val-Ser-Val-Leu-Thr-Val-Leu-His-Gln-Asp-Trp-Leu-Asn-Gly-Lys-Glu-Tyr-Lys- 341 Cys-Lys-Val-Ser-Asn-Lys-Ala-Leu-Pro-Ala-Pro-Ile-Glu-Lys-Thr-Ile-Ser-Lys-Ala-Lys- 361 Gly-Gln-Pro-Arg-Glu-Pro-Gln-Val-Tyr-Thr-Leu-Pro-Pro-Ser-Arg-Glu-Glu-Met-Thr-Lys- 381 Asn-Gln-Val-Ser-Leu-Thr-Cys-Leu-Val-Lys-Gly-Phe-Tyr-Pro-Ser-Asp-Ile-Ala-Val-Glu- 401 Trp-Glu-Ser-Asn-Gly-Gln-Pro-Glu-Asn-Asn-Tyr-Lys-Thr-Thr-Pro-Pro-Val-Leu-Asp-Ser- 421 Asp-Gly-Ser-Phe-Phe-Leu-Tyr-Ser-Lys-Leu-Thr-Val-Asp-Lys-Ser-Arg-Trp-Gln-Gln-Gly- 441 Asn-Val-Phe-Ser-Cys-Ser-Val-Met-His-Glu-Ala-Leu-His-Asn-His-Tyr-Thr-Gln-Lys-Ser- 461 Leu-Ser-Leu-Ser-Pro-Gly-(Lys) 240 246 249 Cys N 149 171 317 Asn O 184Thr 199Ser 200Thr 202Ser 208Thr 212Ser 213Thr 217Thr 218Ser 226Ser 2

2 O NeuAc 2 3 Gal 1 3 GalNAc NeuAc 2 3 Gal 1 3 (NeuAc 2 6) GalNAc GlcNAc 1 2 Man 1 GlcNAc 1 2 Man 1 Fuc 1 Gal 1 4 GlcNAc 1 2 Man 1 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 6 GlcNAc 1 2 Man 1 Fuc 1 Gal 1 4 GlcNAc 1 2 Man 1 Gal 1 4 GlcNAc 1 2 Man 1 Gal 1 4 GlcNAc 1 2 Man 1 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 6 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 Man 1 4 GlcNAc 1 4 GlcNAc 6 Gal 1 4 GlcNAc 1 2 Man 1 Fuc 1 6 3 Gal 1 4 GlcNAc 1 2 Man 1 N NeuAc 2 3 NeuAc 2 3 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 Gal 1 4 GlcNAc 1 2 Man 1 Gal 1 4 GlcNAc 1 2 Man 1 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 6 Gal 1 4 GlcNAc 1 2 Man 1 Fuc 1 NeuAc 2 3 Gal 1 4 GlcNAc 1 2 Man 1 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 NeuAc 2 3 Gal 1 4 GlcNAc 1 2 Man 1 NeuAc 2 3 Gal 1 4 GlcNAc 1 2 Man 1 6 Man 1 4 GlcNAc 1 4 GlcNAc 3 6 NeuAc 2 3 Gal 1 4 GlcNAc 1 2 Man 1 Fuc 1 NeuAc N-, Gal, GlcNAc N-, Man, GalNAc N-, Fuc 3

16 11 5 25mg 14 11 18 1mL 10 25mg 1 1 2 (1) (2) 10mg 25mg 1 (3) 4

(4) 5

16 7 26 25mg 14 11 18 1 25mg 1mL 25mg 1 1 2 16 3 16 4 1 Immunex Amgen IgG 1 Fc 2 CHO (Tumor Necrosis Factor<TNF>) TNF TNF 19 20 ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E5 Rheumatoid Arthritis<RA> 2004 1 67 RA 6

TNFR- 1 235 G 1 γ Fc 236 467 467 C 2224 H 3472 N 618 O 701 S 36 51237.42 cdna CHO C- IgG 1 150,000 mrna cdna p75 TNF TNFR cdna IgG 1 IgG 1 IgG 1 Fc TNF IgG 1 Fc CHO MCB MCB WCB MCB WCB WCB L in vitro A DEAE DV50 ph mg/ml 7

N C SDS- SDS-PAGE pi pi pi SDS-PAGE 76,000 150,000 α- β- TNF-α TNF-α SDS-PAGE N ph SDS-PAGE CHO G A SDS-PAGE< > N <SDS-PAGE > 25mg µm ph ph D- 1mL 1 8

SDS-PAGE phsds-page / γ / / γ N Murine Minute Virus MMV DV50 4 Xenotropic Murine Leukemia Virus Pseudorabies Virus Reovirus Type 3 10 MMV 3 MMV 20 40 nm MMV nm 1. CHO 2. MCB WCB MMV 3. 4. EOPC 9

5. γ N- 1 Pro 2 N- N- N- 1 2 4 5 Pro 2 Ala 3 Val 5 Ala 6 N- Pro 2 Leu 1 Pro 2 Leu 1 /Pro 2 2 Leu 1 /Pro 2 IgG 1 % 10 % / 0.01 % 0.1 % 10

24 G ppm ppm G / γ γ γ γ Leu 1 γ Leu 1 % γ Leu 1 % γ Leu 1 % γ γ Leu 1 % % Pro 2 γ γ γ γ Leu 1 γ γ / WCB WCB MCB WCB MCB WCB WCB 11

WCB ± 3σ G A γ γ γ γ γ γ γ 20 / / /24 5 5 / / /3 ph 5 γ -20 / 12

/ /24 5 5 / / /12 12 1 25 25 / / /2 25 2 5 6 24 36 γ 5 / / /24 25 / / /24 40 / / /18 ph 9 3 γ 25 / /200 W h/m 2 120 Lux h 2 8 2 42 1 ml 5 48 25 24 5 48 25 24 200 W h/m 2 120 Lux h 1 2 13

100 IgG1 Fc 75 KD p75 TNFR-II 2 TNFR:Fc TNF TNF 2 3 2 3 2,000 mg/kg 500 mg/kg 15 mg/kg/day 3 2 4 26 20 2 2 B* T* 2 0 15 B* 15 T* mg/kg/ 2 15 mg/kg/ 4 0 1 5 15 mg/kg/ 15 mg/kg/ 6 1 * 14

26 0 1 5 15 mg/kg/ 4 15 mg/kg/ 9 5 20 0 0.2 2.0 mg/kg/day 2.0 mg/kg/day 6 1 6 20 21 6 21 4 6 18 29 30mg/kg/day 40 mg/kg/day TK 26 26 15

15 mg/kg 15 mg/kg AUC AUC 0-96hr I 25 mg AUC 0-28 41 26 26 16

TNF TNF TNF TNF Kavanaugh AF, Rheum Dis Clin North Am, 24(3): 593-614, 1998 TNF Sugarman Bj et al, Science, 230: 943-945, 1985 Shepard H et al, J Clin Immunol, 8: 333-341, 1988 in vitro T 26 TNF Taniguchi T et al, Lab Invest, 77: 647-658, 1997-20: 160018 RA mbsa 5 µg/joint/day 17

3 0 4 14 10 14 1.0 µg/body/day 0 4 150 µg/body/day 10 0 4 IgG 50 µg/body/day 21 8 0 12 3 28 50 µg/body/day 14 10 µg/body/day 35 3 16 TNF TNFα TNFβ TNFα 3 TNFβ (LT) 1 LTα 2 LTβ 3 LTα1LTβ2LTα 3 LTα3 TNFα LT(LTα3) TNFR TNFα LTα3 T TNFR U937 125 I- TNF TNFR Ki 1 10-10 M TNFR 50 TNFR TNF 0.01 ng/ml 100 µg/ml TNF TNF TNF 10 ng/ml 30 100 µg/body IL-1α TNF 24 10/10 6 10 10 µg/body LPS 18

5 50 %100 µg/body LPS 2 3 LPS 4 LPS 100 µg/body LPS TNF in vitro TNF in vivo TNF TNF LTα p55 p75tnf Idriss HT & Naismith JH, Microsc Res Tech, 50: 184-195, 2000 TNF LTα 1 3 TNFα 1 3 LTα3 Scallon B et al, J. Pharmacol Exp Ther, 301: 418-426, 2002 TNF TNF TNFR TNF 15, 50, 150 mg/kg, 5, 15, 50 mg/kg, 100 µg /ml 1, 3, 10, 15, 30 mg/kg, 5, 15, 50 mg/kg, 5, 15, 50 mg/kg, 10 mg/kg 30 30 60 R 1 3 mg/kg 15 mg/kg 5 10 24 1 0.01 0.1 1 mg/ml CD4 T (PLP7) 200 µg/ / 3 0, 0.5, 1, 2, 3, 4, 4.5, 5 T 15 30 µg/ml 19

Th1 IFNγ IL-12 IL-2 Th2 IL-10 Becher B et al, J Immunol, 162: 684-688, 1999 IFNγ TNF TNFα LTα TNFα LTα Roach DR et al, J Exp Med, 193: 239-246, 2001 Flynn JL et al, Immunity, 2: 561-572, 1995 TNFα TNF RA Th1 SLE Th2 Th1 Th2 Becher B et al, J Immunol, 162: 684-688, 1999 Th2 IFNγ Th1 Th2 Th2 SLE SLE NZB/W F1 TNFα SLE Gordon C et al, Clin Immunol Immunopathol, 52: 421-434, 1989 I NOD TNFα Satoh J et al, J Clin Invest, 84: 1345-1348, 1989 SLE RA MRL/lpr TNFα mrna Takahashi S, Clin Immunol, 22: 1288-1295, 1990 TNF 2 20

2 / t 1/2 18.5 hr 30 102 hr TNF TNFα TNFR TNF-α 157 3 79 % Pennica D et al, Proc Natl Acad Sci USA, 82: 6060-6064, 1985 Fransen L et al, Nucleic Acids Res, 13: 4417-4429, 1985 TNFR-II 461 TNFR-II 162 240 27 173 Gruss HJ & Dower SK, Blood, 85: 3378-3403, 1995 Smith CA et al, Science, 248: 1019-1023, 1990 TNFR-II 73 % 58 % TNF TNFR-I TNFR-II TNF TNFR-I TNFR-II Lewis M et al, Proc Natl Acad Sci USA, 88: 2830-2834, 1991 L929 TNF TNF TNF TNF TNF TNF TNFR TNF TNF TNF TNF 21

10 14 2 35-2 10 14 IgG1 Fc 75 KD p75 TNFR-II 2 TNFR:Fc 1.0 µg/body 0.04 mg/kg TNF 10 30 µg/body 10 µg/body 20 mg/body 25 mg/body 25 mg/body 0.5 mg/kg 300 150 mg/kg 200 mg/kg 12 700 µg/ml in vitro TNF 70000 1000 2000 ng/ml 350 700 100 50 mg/kg 230 µg/ml in vitro TNF 2.3 22

115 230 20 10 mg/kg 70 µg/ml in vitro TNF 7000 35 70 60 30 mg/kg 30 15 mg/kg 10 mg/kg 24 35 µg/ml in vitro TNF 3500 17 35 15 mg/kg 24 94 µg/ml in vitro TNF 9400 47 94 30 9 7 3 28.7 bpm 4 34.7 bpm T max 15 mg/kg 23 24 10.5 24 8 14.9 mmhg2 6.8 mmhg 1 125 I -1 3 23

5 50 mg/kg 5 50 mg/kg 1 15 mg/kg 5 50 mg/kg T max 24 C max 11.0 99.4 µg/ml AUC 0-24hr 119 1088 µg hr/ml 1 15 mg/kg T max 19 31 23 24 C max 5.8 6.2 99 109 µg/ml AUC 0-96hr 373 415 6677 6697 µg hr/ml t 1/2 t 1/2 46 77 2 mg/kg 73 % C max AUC C max AUC 125 I 17 125 I 3 mg/kg 125 I 14 125 I 3 mg/kg 24

5 mg/kg MTX 2.5 mg/kg -1 105-JA -4 6 11 16.9125 16.0010 16.0017 16.0006 RA -2 202-JA -7 8 16.0002 16.0024 RA -9 16.9203 HIV -10 16.0001 Population PK RI PK -11 16.0006-1 105-JA 10 mg 50 mg Tmax CLtot/F t 1/2 44 53 hr 125 153 ml/hr 78 88 hr Cmax AUC 474 2668 ng/ml 76.5 412.0 ng hr/l -2 202-JA RA 10 mg 25 mg 2 4 8 12 10 mg 950 1017 ng/ml 25 mg 2221 2590 ng/ml 4 Cmax 2 10 mg 25 mg PK RA 25

-11 16.0006 131 I 16 mg/m 2-16 100-EU 3 RA TNF -TNF 86±23-11 16.0006 PPK -1 105-JA -2 202-JA RA CL/F 52.3 kg 0.116 L/h 52.3 kg RA 0.0944 L/h PPK CL/F RA CL/F CL/F -2 202-JA PK 7-4 7 9 11 16.9125 16.0010 16.0017 16.0002 16.9203 16.0001 16.0006 3-13 15-6 16.0004 16.0014 16.0016 10 PPK 25 mg 14.5 mg/m 2 Tmax 48 ± 19 Cmax 1.64 ± 0.75 µg/ml 76 % t 1/2 80 CL RA 0.066 L/h RA HIV 0.093 L/h -12 GMR-33321 PPK RA RA PK CL/F RA 0.115 L/h -11 16.0006 0.132 L/h -5 6 16.0010 16.0017 PPK Juvenile Rheumatoid Arthritis<JRA> 4 17 26

-6 16.0016 141 CL/F -9 12 16.9203 GMR-33321 6 P450 PPK MTX MTX -12 GMR-33321 2 B* B T* T 25 mg AUC 235.1 245.2 µg hr/ml 95 % 0.94 1.15 B* T* -6: 16.0017 IgG 1 Fc 75 kda (p75) tumor necrosis factor receptor TNFR 2 in vitro 125 I in vitro 3 27

in vivo p75tnfr Austgulen R et al, J Reprod Immunol 22: 105-116, 1992 30kDa 45 kda Corti A et al, Eur Cytokine Netw 6: 29-35, 1995 78 88 hr 105-JA 30 28 15 6 5 100 10 22 30 IgG 3 Fc Ghetie V et al, Eur J Immunol, 26: 690-696, 1996 5 Fc IgG 15 IgG α- 15 6.6 4 α- 4.4 g/dl α- 62 mg/dl IgG 1250 mg/dl, 31,, p491, 1998 50 mg 2.7 µg/ml α- 100 AUC CL/F 28

AUC 7.5%Cmax AUC / 90% 0.8 1.25 PR QSR QTc MTX AUC 0-72h Day 1 690±35 µg hr/ml Day 11 403±45 µg hr/ml t 1/2 Day 1 30.0±4.6 hr Day 11 10.8±4.5 hr MTX Day 1 MTX Day 11 MTX Day 1 MTX Day 11 AUC 0-72hr t 1/2 RA PPK MTX MTX RA RA -7: 16.0002-13: 16.0004-14: 16.0009-15: 16.0014-18: 16.0012-19: 16.0008-21: 16.0019-6: 16.0016 1164 35 19 RA -4: 16.9125-9: 16.9203-10: 16.0001-16: 100-EU -17: 300-EU -11: 16.0005-14: 16.0605 608 40 202-JA -2 10mg 51 2 25mg 50 2 310-JA 95 5 9 PK EU -16-17 202JA -2 PK 29

4 2 2 822 ng/ml 3 1470 ng/ml 2 ACR20 9 7 ACR20 TNF RA PPK CL/F RA PPK CL/F CL/F 0.0755 1 0.00476 1 0.0126 [L/hr] CL/F CL/F PPK PPK ME PPK -0.0658 PPK 0.00164 PPK 65 65 PPK 0.01008-0.01842 PPK 0.09073 0.27165 PPK RMSE PPK 30

PPK RA PPK RA GCP 6 PPK Complete clinical data package RA -2 202-JA -13 16.0004-14 16.0009ACR 20 % -1 105-JA-2 202-JA -5 16.0010-6 16.0017-8 16.0024-17 300-EU * ACR 20 % :American College of Rheumatology 20 % 1. 2. 3. 4.HAQ Health Assessment Questionnaire 5.CRP C-Reactive Protein ESR Erythrocyte Sedimentation Rate 5 3 20 % ACR 20 % 31

Complete Clinical Data Package -1 105-JA 10mg, 25mg, 50mg N=30( I -4 16.9125) 1 60 mg/m 2 N=32( -5 16.0010 10mg N=6( -6 16.0017 25 mg N=26 ( -7 16.0002 2-32 mg/m 2 N=22 RA 25 mg N=25 RA -10 16.0001 0.125 2.5 mg/m 2 N=13 HIV - 11 16.0006 1-25 mg N=15 8 RA6-16 100-EU 10mgx1W-50mgx2W 4W-8W N=70 RA PPK -12 GMR-33321-9 16.9203-2 202-JA p, 6 mg/m 2 18 mg/m 2, 60 mg/m 2 N=141( P, 10mg, 25mgx2W, 12W, ACR20, -13 16.0004 N=153 (DMARD RA p, 0.25 mg/m 2 2 mg/m 2 16 mg/m 2 N=180 (RA Bridge -14 16.0009 p, 10mgx2, 25mgx2/W ACR20, 26W, N=234(DMARD RA / MTX -15 16.0014 p, 25mgx2 MTX ACR20 26W, N=89 (MTX RA -3 310-JA 25mgx2W, ACR20,50,70, N=126, -1 313-JA 25mgx2W,, N=43 EU -17 300-EU p,10 mg 1, 25mg 1 10mg 2, 25mg 2/W, 12W, N=559 (DMARD RA MTX (EU -22 308-EU MTX, 25mg 2/W AUC-N-ACR, SHARP, 52W, N=682 (DMARD RA -19 16.0008 25mgx2/W, 52W, RA N=105-20 16.0018)10mgx2, 25mgx2/W, 52W 90-21 16.0019 25mgx2/W, 26W, ACR20, N=239 RA I RA PK -1 105-JA 30 10 32

mg 25 mg 50 mg 24 8 3 6 16.7 % 1/6 10 mg 62.5 % 5/8 25 mg 75.0 % 6/8 50 mg 50.0 % 4/8 0.0 % 0/6 10 mg 62.5 % 5/8 25 mg 50 % 4/8 50 mg 12.5 % 1/8 5 10 mg 2 25 mg 2 50 mg 1 2 10 mg 1 25 mg 1 2 10 mg 1 25 mg 1 2 10 mg 1 25 mg 1 CRP 2 10 mg 1 25 mg 1 50 mg : -4 16.9125 Part A: 14 Part B: 18 Part A 6 1, 5, 10, 15, 30 60 mg/m 2 1 2 60 mg/m 2 4 Part B 10 60 mg/m 2 4 ng/kg 6 Part A 1 5 mg/ m 2 1 10 mg/ m 2 2 Part B 100 % 10 mg/m 2 1 60 mg/m 2 1 2 Part A Part B 100 % 32 Part A Part B 14 Part A: 10mg 2 15mg 1 Part B: 6 10mg 2 60mg 3 : 3 4-5 33

60 mg/m 2 : -5 16.0010: Korth-Bradley JM et al, Ann Pharmacother, 34: 161-164, 2000 6 10 mg 50 % 3/6 33.3 % 2/6 2 1 100 % 6/6 10 4 6 6 3 3 : -6 16.0017: Korth-Bradley JM et al, Ann Pharmacother, 34: 161-164, 2000 26 B* <B > T* <T > 25 mg B 38.5 % 10/26 T 38.5 % 10/26 B 30.8 % 8/26 T 30.8 % 8/26 9 B 4 T 5 : 1 3 B 2 T 1 2 1 2 1 B 50.0 % 13/26 T 30.8 % 8/26 6 B 5 T 1 5 B 4 T 1 AST(GOT) 5 B 1 T 4 3 B 1 T 2 : 1 34

RA RA : -7 16.0002: Moreland LW et al, J Rheumatol, 23: 1849-1855, 1996 RA 22 4 8 16 32 mg/m 2 2 8 1 1 4 3 16/8 mg/m 2 1 32/16 mg/m 2 75.0 % 3/4 4/2 mg/m 2 83.3 % 5/6 8/4 mg/m 2 100 % 3/3 16/8 mg/m 2 83.3 % 5/6 32/16 mg/m 2 85.7 % 6/7 32/16 mg/m 2 1 25 % 1/4 4/2 mg/m 2 33.3 % 2/6 8/4 mg/m 2 33.3 % 1/3 16/8 mg/m 2 33.3 % 2/6 32/16 mg/m 2 57.1 % 4/7 8 4/2 mg/m 2 2 8/4 mg/m 2 1 16/8 mg/m 2 1 32/16 mg/m 2 4 24 4 4/2 mg/m 2 5 8/4 mg/m 2 3 16/8 mg/m 2 6 32/16 mg/m 2 6 17 2 4/2 mg/m 2 4 8/4 mg/m 2 2 16/8 mg/m 2 4 32/16 mg/m 2 5 16 3 4/2 mg/m 2 3 8/4 mg/m 2 2 16/8 mg/m 2 5 32/16 mg/m 2 3 13 3 4/2 mg/m 2 2 8/4 mg/m 2 1 16/8 mg/m 2 3 32/16 mg/m 2 4 32 mg/m 2 RA : -8 16.0024: Lee H et al, Clin Pharmacol Therapeut, 73: 348-365, 2003 RA 25 25 mg 2/ 24 35

84 % 21/25 28.0 % 7/25 48 % 12/25 60.0 % 15/25 6 4 4 3 24 % 6/25 8 92.0 % 23/25 10 8 7 6 24 : -11 16.0006 8 1 RA6 15 Part A I 125 1 2 4 8 16 mg/m 2 Part B I 131 16 mg/m 2 Part C I 125 10 25 mg Part A 62.5 % 5/8 Part B 100 % 1/1 Part C 10 mg 100 % 3/3 25 mg 0 % 0/3 Part A 1 mg/m 2 2 mg/m 2 8 mg/m 2 16 mg/m 2 1 4 Part B 1 Part C 10 mg 1 Part A 50.0 % 4/8 Part B 100 % 1/1 Part C 10 mg 25 mg 100 % 3/3 5 4 3 RA : -16 100-EU RA 70 36

10mg 1/ 2/ 50 mg 1/2 50 mg 1/ 2/ 4 5 % 18 % 10 mg 1/ 27 % 0 % 10 mg 2/ 40 % 40 % 50 mg 1/2 13 % 47 % 50 mg 1/ 40 % 29 % 50 mg 2/ 57 % 50 % 2 µg/ml Treatment Emergent Adverse Event<TEAE> 50.0 % 7/14 10 mg 1/ 81.8 % 9/11 10 mg 2/ 73.3 % 11/15 50 mg 1/2 66.7 % 6/9 50 mg 1/ 77.8 % 7/9 50 mg 2/ 83.3 % 10/12 10 mg 1/ 1 10 mg 2/ 1 1 2 50 mg 2/ 1 10 mg 1/ 21.4 % 3/14 10 mg 1/ 63.6 % 7/11 10 mg 2/ 46.7 % 7/15 50 mg 1/2 66.7 % 6/9 50 mg 1/ 77.8 % 7/9 50 mg 2/ 75.0 % 9/12 19 10 mg 2/ 3 50 mg 1/2 4 50 mg 1/ 4 50 mg 2/ 8 5 2 10 mg 1/ 1 10 mg 2/ 1 50 mg 1/ 1 5 1 10 mg 1/ 3 50 mg 1/ 1 5 1 10 mg 1/ 1 50 mg 1/2 2 50 mg 2/ 1 4 10 mg 1/ 2 50 mg 1/2 2 100 % 14/14 10 mg 1/ 90.9 % 10/11 10 mg 2/ 73.3 % 11/15 50 mg 1/2 100 % 9/9 50 mg 1/ 100 % 9/9 50 mg 2/ 100 % 12/12 47 11 10 mg 1/ 8 10 mg 2/ 7 50 mg 1/2 7 50 mg 1/ 8 50 mg 2/ 6 37 7 10 mg 1/ 3 10 mg 2/ 8 50 mg 1/2 6 50 mg 1/ 6 50 mg 2/ 7 ALP 17 5 10 mg 1/ 3 10 mg 2/ 3 50 mg 1/2 2 50 mg 1/ 3 50 mg 2/ 1 12 1 10 mg 1/ 4 10 mg 2/ 2 50 mg 1/2 2 50 mg 1/ 3 56 10 46 15 0 15 67 41.7 % 5/12 10 mg 1/ 72.7 % 8 /11 10 mg 2/ 46.7 % 7/15 50 mg 1/2 66.7 % 6/9 50 mg 1/ 62.5 % 5/8 50 mg 2/ 58.3 % 7/12 ds-dna 50 mg 2/ 1 37

-9 16.9203: Fisher CJ et al, N Engl J Med, 334: 1697-1702, 1996 141 2 0.15 0.45 1.5 mg/kg 10 30 100 mg 28 30 % 10/33 0.15 mg/kg 30 % 9/30 0.45 mg/kg 48 % 14/29 1.5 mg/kg 53 % 26/49 p=0.016 100 % 33/33 0.15 mg/kg 93.3 % 28/30 0.45 mg/kg 100 % 29/29 1.5 mg/kg 98.0 % 48/49 33.3 % 11/33 0.15 mg/kg 30.0 % 9/30 0.45 mg/kg 48.3 % 14/29 1.5 mg/kg 53.1 % 26/49 1.5 mg/kg 1 15.2 % 5/33 0.15 mg/kg 23.3 % 7/30 0.45 mg/kg 3.4 % 1/29 1.5 mg/kg 16.3 % 8/49 4 2 0.15 mg 1 1.5 mg 1 1 39.4 % 13/33 0.15 mg/kg 26.7 % 8/30 0.45 mg/kg 27.6 % 8/29 1.5 mg/kg 36.7 % 18/49 19 5 0.15 mg/kg 5 0.45 mg/kg 2 1.5 mg/kg 7 5 1 1.5 mg/kg 4 4 2 0.45 mg/kg 1.5 mg/kg 1 100 % 139 100 % 136 0.15mg/kg : <33 30 > 0.45mg/kg 27 1.5 mg/kg 46 132 33 0.15mg/kg 28 0.45mg/kg 26 1.5 mg/kg 45 84 22 62 13 4 9 38

HIV : -10 16.0001 HIV 13 I 0.25 mg/m 2 +2 0.125 mg/m 2 1 mg/m 2 +2 0.5 mg/m 2 2.5 mg/m 2 +2 1.25 mg/m 2 2/ 8 100 % 500 µg/m 2 1 100 % 8 I 1 3 4 7 I 1 2 4 7 3 4 7 I 2 2 3 AST(GOT) 6 I 1 2 3 100 % 12 I 3 4 5 11 I 2 4 5 AST(GOT) 11 I 2 3 6 HIV DMARD -2 202-JA DMARD Disease Modifying Anti-Rheumatic Drugs RA 50 150 10 mg 25 mg 2 / DMARD 4 12 153 50 10 mg 52 25 mg 51 GCP 1 GCP 6 147 48 10 mg 50 25 mg 49 GCP 39

3 ACR20 6.3 % 3/48 10 mg 64.0 % 32/50 25 mg 65.3 % 32/49 Cochran-Armitage p<0.001; 2.5% 25 mg Fisher p<0.001 10 mg 25 mg ACR50 ACR70 3 ACR20 74.0 % 37/50 10 mg 75.0 % 39/52 25 mg 76.5 % 39/51 25 mg 1 25 mg 68 12 19 RA 21 25 mg 1 54.0 % 27/50 10 mg 69.2 % 36/52 25 mg 60.8 % 31/51 (n=50) 10 mg (n=52) 25 mg (n=51) 27 (54 %) 36 (69.2 %) 31 (60.8 %) 0 (0.0 %) 8 (15.4 %) 8 (15.7 %) 6 (12.0 %) 7 (13.5 %) 6 (11.8 %) 0 (0.0 %) 3 (5.8 %) 5 (9.8 %) NOS 3 (6.0 %) 2 (3.8 %) 2 (3.9 %) NOS 0 (0 %) 4 (7.7 %) 1 (2.0 %) NOS 1 (2.0 %) 2 (3.8 %) 1 (2.0 %) ALT(GPT) 1 (2.0 %) 2 (3.8 %) 1 (2.0 %) 0 (0.0 %) 1 (1.9 %) 2 (3.9 %) 0 (0.0 %) 2 (3.8 %) 1 (2.0 %) 0 (0.0 %) 2 (3.8 %) 1 (2.0 %) 40

150 49 10 mg 51 25 mg 50 4 10 mg 25 mg 2 152 49 10 mg 52 25 mg 51 63.3 % 31/49 10 mg 67.3 % 35/52 25 mg 66.7 % 34/52 ds-dna 10 mg 3 DMARD : -13 16.0004: Moreland LW et al, N Engl J Med, 337: 141-147, 1997 DMARD RA 45 180 0.25 mg/m 2 2 mg/m 2 16 mg/m 2 2 DMARD 4 12 1.83 m 2 0.25 mg/m 2 2 mg/m 2 16 mg/m 2 0.45 mg 3.7 mg 30 mg 180 44 0.25 mg/m 2 46 2 mg/m 2 46 16 mg/m 2 44 3 [ last nomissing value ]; p=0.006 0.002 0.002 3 25 % 0.25 mg/m 2 22 % 2 mg/m 2 40 % 16 mg/m 2 61 % 16 mg/m 2 LSD ; 5% 68.2 % 30/44 0.25 mg/m 2 71.7 % 33/46 2 mg/m 2 82.6 % 38/46 16 mg/m 2 95.5 % 42/44 1 0.25 mg/m 2 1 0.25 mg/m 2 1 2 mg/m 2 Clayton 1 16 mg/m 2 RA 1 10 41

18.2 % 8/44 0.25 mg/m 2 21.7 % 10/46 2 mg/m 2 26.1 % 12/46 16 mg/m 2 72.7 % 32/44 0.25mg/m 2 2mg/m 2 16mg/m 2 N=44 N=46 N=46 N=44 8(18.2%) 10(21.7%) 12(26.1%) 32(72.7%) 3(6.8%) 2(4.3%) 6(13.0%) 23(52.3%) 1(2.3%) 1(2.2%) 2(4.3%) 2(4.5%) 1(2.3%) 4(8.7%) 0(0.0%) 1(2.3%) 0(0.0%) 1(2.2%) 1(2.2%) 2(4.5%) 1(2.3%) 1(2.2%) 0(0.0%) 1(2.3%) 0(0.0%) 0(0.0%) 1(2.2%) 2(4.5%) 0(0.0%) 1(2.2%) 1(2.2%) 0(0.0%) 0(0.0%) 0(0.0%) 0(0.0%) 2(4.5%) 0(0.0%) 1(2.2%) 1(2.2%) 0(0.0%) 0(0.0%) 1(2.2%) 0(0.0%) 1(2.3%) 0(0.0%) 0(0.0%) 1(2.2%) 1(2.3%) 27.3 % 12/44 0.25 mg/m 2 43.5 % 20/46 2 mg/m 2 34.8 % 16/46 16 mg/m 2 45.5 % 20/44 9 2 0.25 mg/m 2 2 2 mg/m 2 4 16 mg/m 2 1 9 2 0.25 mg/m 2 2 2 mg/m 2 4 16 mg/m 2 1 8 1 0.25 mg/m 2 4 2 mg/m 2 3 8 1 0.25 mg/m 2 4 2 mg/m 2 3 7 1 0.25 mg/m 2 3 2 mg/m 2 2 16 mg/m 2 1 7 0.25 mg/m 2 4 16 mg/m 2 3 126 DMARD RA 16 mg/m 2 16 mg/m 2 DMARD -14 16.0009: Moreland LW et al, Ann Intern Med, 130: 478-486, 1999 Lee H et al, Clin Pharmacol Therapeut, 73: 348-365, 2003 DMARD RA 75 225 10 mg 25 mg 2 DMARD 4 26 234 42

3 ACR20 23 % 10 mg 45 % 25 mg 62 % χ 2 : 10 mg : p=0.003 25 mg : p<0.001 25 mg 10 mg χ 2 ; p<0.001 p=0.036 3 ACR50 25 mg % p * 10 mg 25 mg vs. vs. 10 mg vs. n=80 (n=76) (n=78) 10 mg 25 mg 25 mg ACR20 3 23 % (18) 45 % (34) 62 % (48) 0.003 <0.001 0.036 6 11 % (9) 51 % (39) 59 % (46) <0.001 <0.001 0.339 ACR50 3 8 % (6) 13 % (10) 41 % (32) 0.243 <0.001 <0.001 6 5 % (4) 24 % (18) 40 % (31) <0.001 <0.001 0.032 *: χ 55 % 44/80 10 mg 81.6 % 62/76 25 mg 71.8 % 56/78 12.5 % 10/80 10 mg 43.4 % 33/76 25 mg 48.7 % 38/78 37.5 % 30/80 10 mg 56.6 % 43/76 25 mg 57.7 % 45/78 10 mg 1 25 mg RA 1 5 11.3 % 9/80 10 mg 28.9 % 22/76 25 mg 25.6 % 20/78 10mg 25mg N=80 N=76 N=78 9(11.3%) 22(28.9%) 20(25.6%) 3(3.8%) 4(5.3%) 4(5.1%) 2(2.5%) 2(2.6%) 3(3.8%) 0(0.0%) 2(2.6%) 2(2.6%) 1(1.3%) 2(2.6%) 2(2.6%) 2(2.5%) 3(3.9%) 1(1.3%) 1(1.3%) 1(1.3%) 3(3.8%) 1(1.3%) 2(2.6%) 1(1.3%) 2(2.5%) 2(2.6%) 1(1.3%) 1(1.3%) 1(1.3%) 1(1.3%) 0(0.0%) 1(1.3%) 1(1.3%) 12.5 % 10/80 10 mg 43.4 % 33/76 25 mg 47.4 % 37/78 61 13 10 mg22 25 mg 26 26 9 10 mg 8 25 mg 9 14 4 43

10 mg 7 25 mg 3 11 2 10 mg 7 25 mg 2 10 2 10 mg 6 25 mg 2 7 10 mg 3 25 mg 4 90.0 % 72/80 10 mg 82.9 % 63/76 25 mg 82.1 % 64/78 156 58 10 mg 50 25 mg 48 121 42 10 mg 41 25 mg 38 66 26 10 mg 26 25 mg 14 ALT(GPT) 37 10 10 mg 14 25 mg 13 AST(GOT) 28 8 10 mg 11 25 mg 9 25 mg 279 1 56 : 0920 10 mg 1 231 78 10 mg 75 25 mg 78 20.5 % 16/78 10 mg 36.0 % 27/75 25 mg 26.9 % 21/78 ds-dna 7.7 % 6/78 10 mg 16.0 % 12/75 25 mg 20.5 % 16/78 25 mg DMARD : -17 300-EU DMARD RA 80 400 1/ 2/ 10 mg 1/ 25 mg 1/ 10 mg 2/ 25 mg 2/ 4 DMARD 4 12 559 3 10 mg 1/ 3 10 mg 1/ 10 mg 2/ 25 mg 1/ 25 mg 2/ (n=104) (n=121) (n=110) (n=111) (n=111) (%) 16 43 a 50 a 53 a,b 57 a,b (%) 18 37 a 51 a,b 55 a,b 53 a,b a p 0.0125 vs. (Bonferroni ), b p 0.05 vs. 10 mg 1/, c p 0.05 vs. 10 mg 2/ 44