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- あきたけ こうだ
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1 mg mg 1 150, : tumor necrosis factor receptor (human) fusion protein with immunoglobulin G1 (human γ1-chain Fc fragment), dimmer : : G 1 γ1 Fc 467 C 2224 H 3472 N 618 O 701 S 36 51, 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
2 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) Cys N Asn O 184Thr 199Ser 200Thr 202Ser 208Thr 212Ser 213Thr 217Thr 218Ser 226Ser 2
3 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 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 Gal 1 4 GlcNAc 1 2 Man 1 N NeuAc 2 3 NeuAc 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
4 mg mL 10 25mg (1) (2) 10mg 25mg 1 (3) 4
5 (4) 5
6 mg mg 1mL 25mg Immunex Amgen IgG 1 Fc 2 CHO (Tumor Necrosis Factor<TNF>) TNF TNF ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E5 Rheumatoid Arthritis<RA> RA 6
7 TNFR G 1 γ Fc C 2224 H 3472 N 618 O 701 S 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
8 N C SDS- SDS-PAGE pi pi pi SDS-PAGE 76, ,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
9 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 nm MMV nm 1. CHO 2. MCB WCB MMV EOPC 9
10 5. γ N- 1 Pro 2 N- N- N 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
11 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
12 WCB ± 3σ G A γ γ γ γ γ γ γ 20 / / / / / /3 ph 5 γ -20 / 12
13 / / / / / / / / γ 5 / / /24 25 / / /24 40 / / /18 ph 9 3 γ 25 / /200 W h/m Lux h ml W h/m Lux h
14 100 IgG1 Fc 75 KD p75 TNFR-II 2 TNFR:Fc TNF TNF ,000 mg/kg 500 mg/kg 15 mg/kg/day B* T* B* 15 T* mg/kg/ 2 15 mg/kg/ mg/kg/ 15 mg/kg/ 6 1 * 14
15 mg/kg/ 4 15 mg/kg/ mg/kg/day 2.0 mg/kg/day mg/kg/day 40 mg/kg/day TK
16 15 mg/kg 15 mg/kg AUC AUC 0-96hr I 25 mg AUC
17 TNF TNF TNF TNF Kavanaugh AF, Rheum Dis Clin North Am, 24(3): , 1998 TNF Sugarman Bj et al, Science, 230: , 1985 Shepard H et al, J Clin Immunol, 8: , 1988 in vitro T 26 TNF Taniguchi T et al, Lab Invest, 77: , : RA mbsa 5 µg/joint/day 17
18 µg/body/day µg/body/day IgG 50 µg/body/day µg/body/day µg/body/day TNF TNFα TNFβ TNFα 3 TNFβ (LT) 1 LTα 2 LTβ 3 LTα1LTβ2LTα 3 LTα3 TNFα LT(LTα3) TNFR TNFα LTα3 T TNFR U I- TNF TNFR Ki M TNFR 50 TNFR TNF 0.01 ng/ml 100 µg/ml TNF TNF TNF 10 ng/ml µg/body IL-1α TNF 24 10/ µg/body LPS 18
19 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: , 2000 TNF LTα 1 3 TNFα 1 3 LTα3 Scallon B et al, J. Pharmacol Exp Ther, 301: , 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 R 1 3 mg/kg 15 mg/kg mg/ml CD4 T (PLP7) 200 µg/ / 3 0, 0.5, 1, 2, 3, 4, 4.5, 5 T µg/ml 19
20 Th1 IFNγ IL-12 IL-2 Th2 IL-10 Becher B et al, J Immunol, 162: , 1999 IFNγ TNF TNFα LTα TNFα LTα Roach DR et al, J Exp Med, 193: , 2001 Flynn JL et al, Immunity, 2: , 1995 TNFα TNF RA Th1 SLE Th2 Th1 Th2 Becher B et al, J Immunol, 162: , 1999 Th2 IFNγ Th1 Th2 Th2 SLE SLE NZB/W F1 TNFα SLE Gordon C et al, Clin Immunol Immunopathol, 52: , 1989 I NOD TNFα Satoh J et al, J Clin Invest, 84: , 1989 SLE RA MRL/lpr TNFα mrna Takahashi S, Clin Immunol, 22: , 1990 TNF 2 20
21 2 / t 1/ hr hr TNF TNFα TNFR TNF-α % Pennica D et al, Proc Natl Acad Sci USA, 82: , 1985 Fransen L et al, Nucleic Acids Res, 13: , 1985 TNFR-II 461 TNFR-II Gruss HJ & Dower SK, Blood, 85: , 1995 Smith CA et al, Science, 248: , 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: , 1991 L929 TNF TNF TNF TNF TNF TNF TNFR TNF TNF TNF TNF 21
22 IgG1 Fc 75 KD p75 TNFR-II 2 TNFR:Fc 1.0 µg/body 0.04 mg/kg TNF µg/body 10 µg/body 20 mg/body 25 mg/body 25 mg/body 0.5 mg/kg mg/kg 200 mg/kg µg/ml in vitro TNF ng/ml mg/kg 230 µg/ml in vitro TNF
23 mg/kg 70 µg/ml in vitro TNF mg/kg mg/kg 10 mg/kg µg/ml in vitro TNF mg/kg µg/ml in vitro TNF bpm bpm T max 15 mg/kg mmhg2 6.8 mmhg I
24 5 50 mg/kg 5 50 mg/kg 1 15 mg/kg 5 50 mg/kg T max 24 C max µg/ml AUC 0-24hr µg hr/ml 1 15 mg/kg T max C max µg/ml AUC 0-96hr µg hr/ml t 1/2 t 1/ mg/kg 73 % C max AUC C max AUC 125 I I 3 mg/kg 125 I I 3 mg/kg 24
25 5 mg/kg MTX 2.5 mg/kg JA RA JA RA HIV Population PK RI PK JA 10 mg 50 mg Tmax CLtot/F t 1/ hr ml/hr hr Cmax AUC ng/ml ng hr/l JA RA 10 mg 25 mg mg ng/ml 25 mg ng/ml 4 Cmax 2 10 mg 25 mg PK RA 25
26 I 16 mg/m EU 3 RA TNF -TNF 86± PPK JA JA RA CL/F 52.3 kg L/h 52.3 kg RA L/h PPK CL/F RA CL/F CL/F JA PK 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 L/h RA HIV L/h -12 GMR PPK RA RA PK CL/F RA L/h L/h PPK Juvenile Rheumatoid Arthritis<JRA>
27 CL/F GMR P450 PPK MTX MTX -12 GMR B* B T* T 25 mg AUC µg hr/ml 95 % B* T* -6: IgG 1 Fc 75 kda (p75) tumor necrosis factor receptor TNFR 2 in vitro 125 I in vitro 3 27
28 in vivo p75tnfr Austgulen R et al, J Reprod Immunol 22: , kDa 45 kda Corti A et al, Eur Cytokine Netw 6: 29-35, hr 105-JA IgG 3 Fc Ghetie V et al, Eur J Immunol, 26: , Fc IgG 15 IgG α α- 4.4 g/dl α- 62 mg/dl IgG 1250 mg/dl, 31,, p491, mg 2.7 µg/ml α- 100 AUC CL/F 28
29 AUC 7.5%Cmax AUC / 90% PR QSR QTc MTX AUC 0-72h Day 1 690±35 µg hr/ml Day ±45 µg hr/ml t 1/2 Day ±4.6 hr Day ±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: : : : : : : : RA -4: : : : 100-EU -17: 300-EU -11: : JA -2 10mg mg JA PK EU JA -2 PK 29
30 ng/ml ng/ml 2 ACR ACR20 TNF RA PPK CL/F RA PPK CL/F CL/F [L/hr] CL/F CL/F PPK PPK ME PPK PPK PPK PPK PPK PPK RMSE PPK 30
31 PPK RA PPK RA GCP 6 PPK Complete clinical data package RA JA ACR 20 % JA JA EU * ACR 20 % :American College of Rheumatology 20 % HAQ Health Assessment Questionnaire 5.CRP C-Reactive Protein ESR Erythrocyte Sedimentation Rate % ACR 20 % 31
32 Complete Clinical Data Package JA 10mg, 25mg, 50mg N=30( I ) 1 60 mg/m 2 N=32( mg N=6( mg N=26 ( mg/m 2 N=22 RA 25 mg N=25 RA mg/m 2 N=13 HIV mg N=15 8 RA EU 10mgx1W-50mgx2W 4W-8W N=70 RA PPK -12 GMR JA p, 6 mg/m 2 18 mg/m 2, 60 mg/m 2 N=141( P, 10mg, 25mgx2W, 12W, ACR20, N=153 (DMARD RA p, 0.25 mg/m 2 2 mg/m 2 16 mg/m 2 N=180 (RA Bridge p, 10mgx2, 25mgx2/W ACR20, 26W, N=234(DMARD RA / MTX p, 25mgx2 MTX ACR20 26W, N=89 (MTX RA JA 25mgx2W, ACR20,50,70, N=126, JA 25mgx2W,, N=43 EU EU p,10 mg 1, 25mg 1 10mg 2, 25mg 2/W, 12W, N=559 (DMARD RA MTX (EU EU MTX, 25mg 2/W AUC-N-ACR, SHARP, 52W, N=682 (DMARD RA mgx2/W, 52W, RA N= )10mgx2, 25mgx2/W, 52W mgx2/W, 26W, ACR20, N=239 RA I RA PK JA
33 mg 25 mg 50 mg % 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/ mg 2 25 mg 2 50 mg mg 1 25 mg mg 1 25 mg mg 1 25 mg 1 CRP 2 10 mg 1 25 mg 1 50 mg : Part A: 14 Part B: 18 Part A 6 1, 5, 10, 15, mg/m mg/m 2 4 Part B mg/m 2 4 ng/kg 6 Part A 1 5 mg/ m mg/ m 2 2 Part B 100 % 10 mg/m mg/m Part A Part B 100 % 32 Part A Part B 14 Part A: 10mg 2 15mg 1 Part B: 6 10mg 2 60mg 3 :
34 60 mg/m 2 : : Korth-Bradley JM et al, Ann Pharmacother, 34: , mg 50 % 3/ % 2/ % 6/ : : Korth-Bradley JM et al, Ann Pharmacother, 34: , 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 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
35 RA RA : : Moreland LW et al, J Rheumatol, 23: , 1996 RA mg/m /8 mg/m /16 mg/m % 3/4 4/2 mg/m % 5/6 8/4 mg/m % 3/3 16/8 mg/m % 5/6 32/16 mg/m % 6/7 32/16 mg/m % 1/4 4/2 mg/m % 2/6 8/4 mg/m % 1/3 16/8 mg/m % 2/6 32/16 mg/m % 4/7 8 4/2 mg/m 2 2 8/4 mg/m /8 mg/m /16 mg/m /2 mg/m 2 5 8/4 mg/m /8 mg/m /16 mg/m /2 mg/m 2 4 8/4 mg/m /8 mg/m /16 mg/m /2 mg/m 2 3 8/4 mg/m /8 mg/m /16 mg/m /2 mg/m 2 2 8/4 mg/m /8 mg/m /16 mg/m mg/m 2 RA : : Lee H et al, Clin Pharmacol Therapeut, 73: , 2003 RA mg 2/ 24 35
36 84 % 21/ % 7/25 48 % 12/ % 15/ % 6/ % 23/ : RA6 15 Part A I mg/m 2 Part B I mg/m 2 Part C I 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 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/ RA : EU RA 70 36
37 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/ % 6/9 50 mg 1/ 77.8 % 7/9 50 mg 2/ 83.3 % 10/12 10 mg 1/ 1 10 mg 2/ 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/ % 6/9 50 mg 1/ 77.8 % 7/9 50 mg 2/ 75.0 % 9/ mg 2/ 3 50 mg 1/ mg 1/ 4 50 mg 2/ mg 1/ 1 10 mg 2/ 1 50 mg 1/ mg 1/ 3 50 mg 1/ mg 1/ 1 50 mg 1/ mg 2/ mg 1/ 2 50 mg 1/ % 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/ mg 1/ 8 10 mg 2/ 7 50 mg 1/ mg 1/ 8 50 mg 2/ mg 1/ 3 10 mg 2/ 8 50 mg 1/ mg 1/ 6 50 mg 2/ 7 ALP mg 1/ 3 10 mg 2/ 3 50 mg 1/ mg 1/ 3 50 mg 2/ mg 1/ 4 10 mg 2/ 2 50 mg 1/ mg 1/ % 5/12 10 mg 1/ 72.7 % 8 /11 10 mg 2/ 46.7 % 7/15 50 mg 1/ % 6/9 50 mg 1/ 62.5 % 5/8 50 mg 2/ 58.3 % 7/12 ds-dna 50 mg 2/ 1 37
38 : Fisher CJ et al, N Engl J Med, 334: , mg/kg mg % 10/ mg/kg 30 % 9/ mg/kg 48 % 14/ mg/kg 53 % 26/49 p= % 33/ mg/kg 93.3 % 28/ mg/kg 100 % 29/ mg/kg 98.0 % 48/ % 11/ mg/kg 30.0 % 9/ mg/kg 48.3 % 14/ mg/kg 53.1 % 26/ mg/kg % 5/ mg/kg 23.3 % 7/ mg/kg 3.4 % 1/ mg/kg 16.3 % 8/ mg mg % 13/ mg/kg 26.7 % 8/ mg/kg 27.6 % 8/ mg/kg 36.7 % 18/ mg/kg mg/kg mg/kg mg/kg mg/kg 1.5 mg/kg % % mg/kg : <33 30 > 0.45mg/kg mg/kg mg/kg mg/kg mg/kg
39 HIV : HIV 13 I 0.25 mg/m mg/m 2 1 mg/m mg/m mg/m mg/m 2 2/ % 500 µg/m % 8 I I I AST(GOT) 6 I % 12 I I AST(GOT) 11 I HIV DMARD JA DMARD Disease Modifying Anti-Rheumatic Drugs RA mg 25 mg 2 / DMARD mg mg 51 GCP 1 GCP mg mg 49 GCP 39
40 3 ACR % 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< mg 25 mg ACR50 ACR70 3 ACR % 37/50 10 mg 75.0 % 39/52 25 mg 76.5 % 39/51 25 mg 1 25 mg RA mg % 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
41 mg mg mg 25 mg mg mg % 31/49 10 mg 67.3 % 35/52 25 mg 66.7 % 34/52 ds-dna 10 mg 3 DMARD : : Moreland LW et al, N Engl J Med, 337: , 1997 DMARD RA mg/m 2 2 mg/m 2 16 mg/m 2 2 DMARD m mg/m 2 2 mg/m 2 16 mg/m mg 3.7 mg 30 mg mg/m mg/m mg/m [ last nomissing value ]; p= % 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/ mg/m % 33/46 2 mg/m % 38/46 16 mg/m % 42/ mg/m mg/m mg/m 2 Clayton 1 16 mg/m 2 RA
42 18.2 % 8/ mg/m % 10/46 2 mg/m % 12/46 16 mg/m % 32/ mg/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/ mg/m % 20/46 2 mg/m % 16/46 16 mg/m % 20/ mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m DMARD RA 16 mg/m 2 16 mg/m 2 DMARD : Moreland LW et al, Ann Intern Med, 130: , 1999 Lee H et al, Clin Pharmacol Therapeut, 73: , 2003 DMARD RA mg 25 mg 2 DMARD
43 3 ACR20 23 % 10 mg 45 % 25 mg 62 % χ 2 : 10 mg : p= mg : p< mg 10 mg χ 2 ; p<0.001 p= 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 ACR % (18) 45 % (34) 62 % (48) < % (9) 51 % (39) 59 % (46) <0.001 < ACR % (6) 13 % (10) 41 % (32) <0.001 < % (4) 24 % (18) 40 % (31) <0.001 < *: χ 55 % 44/80 10 mg 81.6 % 62/76 25 mg 71.8 % 56/ % 10/80 10 mg 43.4 % 33/76 25 mg 48.7 % 38/ % 30/80 10 mg 56.6 % 43/76 25 mg 57.7 % 45/78 10 mg 1 25 mg RA % 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/ mg22 25 mg mg 8 25 mg
44 10 mg 7 25 mg mg 7 25 mg mg 6 25 mg mg 3 25 mg % 72/80 10 mg 82.9 % 63/76 25 mg 82.1 % 64/ mg mg mg mg mg mg 14 ALT(GPT) mg mg 13 AST(GOT) mg mg 9 25 mg : mg mg mg % 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 : EU DMARD RA / 2/ 10 mg 1/ 25 mg 1/ 10 mg 2/ 25 mg 2/ 4 DMARD 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) (%) a 50 a 53 a,b 57 a,b (%) a 51 a,b 55 a,b 53 a,b a p vs. (Bonferroni ), b p 0.05 vs. 10 mg 1/, c p 0.05 vs. 10 mg 2/ 44
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2458 13 4 24 1 11 9 17 1,328 C 6426 H 9900 N 1700 O 2008 S 44 145,000 148,000 10 11 27 2 13 4 24 11 9 17 (1) CD20 B CD20 (2) infusion reaction infusion-associated symptom CD20 B 1 375mg/m 2 1 4 3 Heavy
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