(2) タᐃ᰿ᣐ
1.9.3 ᵓ㐀ᘧ
࣑ࣀ㓟㓄ิཬࡧࢪࢫࣝࣇࢻ⤖ྜ㸸 L㙐
H㙐
H㙐E1㸸㒊ศⓗࣆࣟࢢࣝࢱ࣑ࣥ㓟㸹H㙐N302㸸⢾㙐⤖ྜ㸹H㙐K452㸸㒊ศⓗࣉࣟࢭࢩࣥࢢ L㙐C214㸫H㙐C225㸪H㙐C231㸫H㙐C231㸪H㙐C234㸫H㙐C234㸸ࢪࢫࣝࣇࢻ⤖ྜ
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPPTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
EVQLLESGGG LVQPGGSLRL SCAVSGFTFN SFAMSWVRQA PGKGLEWVSA ISGSGGGTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYFCAKDK ILWFGEPVFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK
ࢲࣛࢶ࣒࣐ࣈ 1.9 ୍⯡ⓗྡ⛠ಀࡿᩥ᭩
࡞⢾㙐ࡢ᥎ᐃᵓ㐀㸸
C6466H9996N1724O2010S42㸦ࢱࣥࣃࢡ㉁㒊ศ㸪4ᮏ㙐㸧 H㙐㸸C2204H3404N582O672S16
L㙐㸸C1029H1598N280O333S5
Fuc GlcNAc Man
Gal 0-2 Man GlcNAc GlcNAc GlcNAc Man
ࢲࣛࢶ࣒࣐ࣈ 1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝಀࡿ㈨ᩱࡘ࠸࡚㸪ᮏ⏦ㄳಀࡿෆᐜࢆḟ࣮࣌ࢪࡼࡾ♧ࡍࠋ
ࢲࣛࢶ࣒࣐ࣈ 1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
Ꮫྡ࣭
ูྡ
ࢲࣛࢶ࣒࣐ࣈࡣ㸪ࣄࢺCD38ᑐࡍࡿ㑇ఏᏊ⤌࠼ࣄࢺIgG1ࣔࣀࢡ࣮ࣟࢼࣝᢠయ࡛࠶
ࡿࠋࢲࣛࢶ࣒࣐ࣈࡣ㸪ࢳࣕࢽ࣮ࢬࣁ࣒ࢫࢱ࣮༸ᕢ⣽⬊ࡼࡾ⏘⏕ࡉࢀࡿࠋࢲࣛࢶ࣒
࣐ࣈࡣ㸪452ಶࡢ࣑ࣀ㓟ṧᇶࡽ࡞ࡿH㙐㸦Ț1㙐㸧2ᮏཬࡧ214࣑ࣀ㓟ṧᇶࡽ
࡞ࡿL㙐㸦ȡ㙐㸧2ᮏ࡛ᵓᡂࡉࢀࡿ⢾ࢱࣥࣃࢡ㉁㸦ศᏊ㔞㸸⣙148,000㸧࡛࠶ࡿࠋ 㸦ูྡ㸸ࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧ཬࡧࡑࡢ〇㸧
ᵓ㐀ᘧ ࣑ࣀ㓟㓄ิཬࡧ࡞⢾㙐ࡢ᥎ᐃᵓ㐀ࡣู⣬グ㍕ࡍࡿࠋ
ຠ⬟࣭ຠ
ᯝ
Ⓨཪࡣ㞴ᛶࡢከⓎᛶ㦵㧊⭘
⏝ἲ࣭⏝
㔞
㏻ᖖ㸪ᡂேࡣࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧ࡋ࡚㸪1 ᅇ16 mg/kg ࢆ௨ୗࡢᢞ㛫 㝸࡛Ⅼ㟼ὀࡍࡿࠋ
ࣞࢼࣜࢻ࣑ࢻཬࡧࢹ࢟ࢧ࣓ࢱࢰࣥే⏝ࡢሙྜ㸸
1 㐌㛫㛫㝸㸦1㹼8 㐌┠㸧㸪2㐌㛫㛫㝸㸦9㹼24 㐌┠㸧ཬࡧ4㐌㛫㛫㝸㸦25㐌┠௨㝆㸧
࣎ࣝࢸࢰ࣑ࣈཬࡧࢹ࢟ࢧ࣓ࢱࢰࣥే⏝ࡢሙྜ㸸
1 㐌㛫㛫㝸㸦1㹼9 㐌┠㸧㸪3 㐌㛫㛫㝸㸦10㹼24 㐌┠㸧ཬࡧ4 㐌㛫㛫㝸㸦25 㐌┠௨㝆㸧
⸆➼ࡢ ᣦᐃ ᕷ㈍ྡཬ ࡧ᭷ຠᡂ ศ࣭ศ㔞
ཎయ㸸ࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧
〇㸸ࢲࣛࢨࣞࢵࢡࢫⅬ㟼ὀ100 mg㸦1ࣂࣝ୰㸪ࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌
࠼㸧ࢆ100 mgྵ᭷㸧㸪ࢲࣛࢨࣞࢵࢡࢫⅬ㟼ὀ400mg㸦1ࣂࣝ୰㸪ࢲࣛࢶ
࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧ࢆ400 mgྵ᭷㸧 ẘᛶ ༢ᅇᢞẘᛶ
ື≀✀ ᢞ⤒㊰ ᴫ␎ࡢ⮴Ṛ㔞㸦mg/kg㸧1)
ࢳࣥࣃࣥࢪ࣮ 㟼⬦ෆ ܴܲ㸸5
1) ༢ᅇᢞẘᛶヨ㦂ࢆᐇࡋ࡚࠸࡞࠸ࡓࡵ㸪6㐌㛫ᢞẘᛶヨ㦂ࡢึᅇᢞࡢ⤖ᯝࡽồࡵࡓࠋ
ᢞẘᛶ
ື≀✀ ᢞᮇ㛫 ᢞ⤒㊰
ᢞ㔞 (mg/kg/㐌)
↓ẘᛶ㔞
(mg/kg/㐌) ࡞ᡤぢ
ࢳࣥࣃ
ࣥࢪ࣮
6㐌㛫 (1ᅇ/㐌)
㟼⬦ෆ
0 Ѝ 5 2)
0 Ѝ 25 3) < 5
Ӎ5: Ẽ⟶⢓ᾮЌ㸪౽㸪ዲ୰⌫࣭APTT Ќ㸪ࣜࣥࣃ⌫࣭⾑ᑠᯈ࣭IgG࣭IgMЎ 5: Ṛஸ㸦ܲ1㸧
Ṛஸࡳࡽࢀࡓᡤぢ㸸ࢧࢺ࢝ࣥ
ᨺฟᛂ㸦ࡃࡋࡷࡳ㸪TNF-Į࣭IL-6࣭
IFN-ȖЌ㸪Ẽ⟶ཬࡧ㰯ᏍࡽἻἓ≧ᾮ యࡢ㔞ฟ㸧
25: ࢧࢺ࢝ࣥᨺฟᛂ㸦ࡃࡋࡷࡳ㸪⢓
ᾮЌ㸧㸪⢓⭷ⓑ㸪ୗ⑩㸪㌾౽㸪㣗ḧ పୗ
2) ⁐፹ᢞࡢ1㐌㛫ᚋ㸪ࢲࣛࢶ࣒࣐ࣈ 5 mg/kgࢆ30ศ㛫ࡅ࡚㟼⬦ෆᣢ⥆ᢞ㸦௨ᚋ㸪1㐌㛫ࡈ
ࢲࣛࢶ࣒࣐ࣈ 5 mg/kgࢆィ6ᅇ㸪㟼⬦ෆᣢ⥆ᢞ㸧ࠋ
3) 5 mg/kgࡢึᅇ㟼⬦ෆᣢ⥆ᢞࢧࢺ࢝ࣥᨺฟᛂࡀㄆࡵࡽࢀ㸪㞤1ࡀṚஸࡋࡓࡓࡵ㸪㐣
࡞ࢧࢺ࢝ࣥᨺฟࢆண㜵ࡍࡿ┠ⓗ࡛㸪⁐፹ᢞࡢ2㐌㛫ᚋࢲࣛࢶ࣒࣐ࣈ10 mgࢆ㟼⬦ෆ࣮࣎ࣛ
ࢫ࡛๓ᢞࡋ㸪ࡑࡢ24㛫ᚋࢲࣛࢶ࣒࣐ࣈ 25 mg/kgࢆ1㛫ࡅ࡚㟼⬦ෆᣢ⥆ᢞࠋࢲࣛࢶ࣒࣐
ࣈࡢ2㹼6ᅇ┠ࡢ㟼⬦ෆᣢ⥆ᢞ㛫ࡣ30ศ㛫ࠋ
ࢲࣛࢶ࣒࣐ࣈ 1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
స⏝ స⏝Ⓨ⌧⋡㸦⮫ᗋ᳨ᰝ್␗ᖖࢆྵࡴ㸧 511/ 674㸻75.8%
㹙᪥ᮏࢆྵࡴᅜ㝿ඹྠ➨III ┦ヨ㦂㸦54767414MMY3003 ヨ㦂㸧㸪ᾏእ➨III ┦ヨ㦂 㸦54767414MMY3004 ヨ㦂㸧㸪ᾏእ➨II ┦ヨ㦂㸦54767414MMY2002 ヨ㦂 16mg/kg ࡢࡳ㸧㸪ᾏእ➨I/II ┦ヨ㦂㸦GEN501 ヨ㦂 Part 2 16mg/kgࡢࡳ㸧㹛
స⏝ࡢ✀㢮 ᩘ
Infusion reaction 312/674㸦46.3%㸧
⾑ᑠᯈῶᑡ* 112/674㸦16.6%㸧
⑂ປ* 92/674㸦13.6%㸧 တႿ* 82/674㸦12.2%㸧
྾ᅔ㞴* 79/674㸦11.7%㸧 ዲ୰⌫ῶᑡ 73/674㸦10.8%㸧
ୖẼ㐨ឤᰁ* 73/674㸦10.8%㸧 ᝏᚰ* 63/674㸦9.3%㸧
ୗ⑩* 54/674㸦8.0%㸧
㈋⾑* 53/674㸦7.9%㸧
Ⓨ⇕* 45/674㸦6.7%㸧
ྤ* 45/674㸦6.7%㸧
*Infusion reactionࢆྵࡴ
♫ ࣖࣥࢭࣥࣇ࣮࣐ᰴᘧ♫ 〇㸸〇㐀
ࢲࣛࢶ࣒࣐ࣈ 1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
ู⣬
࣑ࣀ㓟㓄ิཬࡧࢪࢫࣝࣇࢻ⤖ྜ㸸 L㙐
H㙐
H㙐E1㸸㒊ศⓗࣆࣟࢢࣝࢱ࣑ࣥ㓟㸹H㙐N302㸸⢾㙐⤖ྜ㸹H㙐K452㸸㒊ศⓗࣉࣟࢭࢩࣥࢢ㸹 L㙐C214㸫H㙐C225㸪H㙐C231㸫H㙐C231㸪H㙐C234㸫H㙐C234㸸ࢪࢫࣝࣇࢻ⤖ྜ
ࢲࣛࢶ࣒࣐ࣈ 1.10 ẘ⸆࣭⸆➼ࡢᣦᐃᑂᰝ㈨ᩱࡢࡲࡵ
࡞⢾㙐ࡢ᥎ᐃᵓ㐀㸸
Fuc GlcNAc Man
Gal 0-2 Man GlcNAc GlcNAc GlcNAc Man
㸦ู⣬㸧
ู⣬ᵝᘧ㸯
⏕≀⏤᮶་⸆ရཪࡣ≉ᐃ⏕≀⏤᮶་⸆ရࡢᣦᐃ㈨ᩱࡢࡲࡵ
୍⯡ྡ㸸 ࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧
㈍ྡ㸸 ࢲࣛࢨࣞࢵࢡࢫ®Ⅼ㟼ὀ100 mg㸪ྠ400 mg
⏦ㄳ⪅㸸 ࣖࣥࢭࣥࣇ࣮࣐ᰴᘧ♫
ຠ⬟࣭ຠᯝ㸸 Ⓨཪࡣ㞴ᛶࡢከⓎᛶ㦵㧊⭘
⏝ἲ࣭⏝㔞㸸
㏻ᖖࠊᡂேࡣࢲࣛࢶ࣒࣐ࣈ㸦㑇ఏᏊ⤌࠼㸧ࡋ࡚ࠊ1 ᅇ 16 mg/kg ࢆ௨ୗࡢᢞ㛫㝸࡛Ⅼ㟼ὀࡍࡿࠋ
ࣞࢼࣜࢻ࣑ࢻཬࡧࢹ࢟ࢧ࣓ࢱࢰࣥే⏝ࡢሙྜ㸸
1 㐌㛫㛫㝸㸦1㹼8 㐌┠㸧ࠊ2㐌㛫㛫㝸㸦9㹼24 㐌┠㸧ཬࡧ4㐌 㛫㛫㝸㸦25㐌┠௨㝆㸧
࣎ࣝࢸࢰ࣑ࣈཬࡧࢹ࢟ࢧ࣓ࢱࢰࣥే⏝ࡢሙྜ㸸
1 㐌㛫㛫㝸㸦1㹼9 㐌┠㸧ࠊ3 㐌㛫㛫㝸㸦10㹼24 㐌┠㸧ཬࡧ4 㐌㛫㛫㝸㸦25 㐌┠௨㝆㸧
⏕≀⏤᮶ཎᮦᩱࡢ⏝ࡢ᭷↓ ڦ⏝Ѝ ⏝ࡋ࡚࠸ࡿሙྜࡣ௨ୗࡢḍࢆグධ ڧ⏝
⏝ࡋࡓ⏕≀⏤᮶ཎᮦᩱ
ڧே⏤᮶⣽⬊࣭⤌⧊ࠊڧே⏤᮶ᡂศ㸦⾑ᾮࠊᒀࠊࡑࡢ㸧ࠊ ڦື≀⏤᮶⣽⬊࣭⤌⧊ࠊڧື≀⏤᮶ᡂศ㸦⾑ᾮࠊࡑࡢ㸧 ཎᮦᩱྡ㸹ࢳࣕࢽ࣮ࢬࣁ࣒ࢫࢱ࣮༸ᕢ⣽⬊
⏕≀⏤᮶ཎᩱࡢ⏝┠ⓗ ڦᐟ⣽⬊ࠊڧᇵᆅῧຍ≀ࠊڧࡑࡢࡢ〇㐀ཎᮦᩱࠊ ڧ〇ῧຍ≀ࠊڧࡑࡢ㸦 㸧
ཎᮦᩱࡢ⏤᮶࡞ࡿே࣭ື≀ࡢࢫ
ࢡ࣮ࣜࢽࣥࢢ࣭⟶⌮ࡢෆᐜ㸸 ྜ⮴ࡍࡿᇶ‽ࡢ࿌♧࣭㏻▱➼ࡀ࠶ࢀࡤᘬ⏝㸦 㸧 ᙜヱ⏕≀⏤᮶ཎᮦᩱάฎ⌮➼
ࡢෆᐜ㸸 ู⣬ᵝᘧ2ཧ↷
࢘ࣝࢫࢡࣜࣛࣥࢫヨ㦂⤖ᯝࡢ
ᴫせ㸸 ูῧ2ཧ↷
〇㐀ᕤ⛬ࡢᴫせ㸦ࣇ࣮ࣟࢳ࣮ࣕ
ࢺ㸧㸸
㸦άฎ⌮ࡣୗ⥺ࢆࡋࠊฎ
⌮᮲௳ࢆලయⓗグ㍕㸧
ูῧ1ཧ↷
ู⣬ᵝᘧ㸰
⏝ࡋࡓ⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ
ྡ⛠ὀ㸯㸧㸪ὀ㸰㸧 ࢳࣕࢽ࣮ࢬࣁ࣒ࢫࢱ࣮༸ᕢ㸦CHO㸧⣽⬊
⏝ࡋࡓ⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ ศ㢮
ڧே⾑ᾮ⏤᮶ᡂศࠊڧே⣽⬊⤌⧊ࠊڧேᒀ⏤᮶ᡂศࠊڧே⏤
᮶ᡂศ㸦⾑ᾮࠊ⣽⬊⤌⧊ཪࡣᒀࢆ㝖ࡃࡶࡢ㸧ࠊڧⱄື≀⏤
᮶ᡂศࠊڦື≀⣽⬊⤌⧊ࠊ
ڧື≀⏤᮶ᡂศࠊڧࡑࡢ㸦 㸧
⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ⏝┠ⓗ
ڧ〇᭷ຠᡂศࠊڦᐟ⣽⬊ࠊڧᇵᆅῧຍ≀ࠊ
ڧࡑࡢࡢ〇㐀ཎᩱཪࡣᮦᩱ㸦 㸧ࠊڧ〇ῧຍ≀ࠊ ڧࡑࡢ㸦 㸧
⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ⏤᮶࡞
ࡿே࣭ື≀ࡢࢫࢡ࣮ࣜࢽࣥࢢ࣭⟶
⌮ࡢෆᐜὀ㸱㸧
ᐟ⣽⬊㸦CHO⣽⬊㸧ࢆ⏝࠸࡚ࢲࣛࢶ࣒࣐ࣈ⏘⏕⣽⬊ᰴ
ࢆస〇ࡋ㸪MCBཬࡧWCBࢆᵓ⠏ࡋࡓࠋMCBཬࡧ WCBࡣ㸪ICH Q5AཬࡧQ5Dᚑࡗ࡚⣧ᗘヨ㦂ࢆ⾜࠸㸪࠸ࡎ
ࢀࡶ⣽⳦㸪┿⳦㸪࣐ࢥࣉࣛࢬ࣐ཬࡧ࢘ࢩཪࡣእ᮶ᛶ࢘ࣝ
ࢫࡢΰධࡣㄆࡵࡽࢀ࡞ࡗࡓࠋ
⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ࢘ࣝࢫ
➼ࡢάཬࡧ㝖ཤฎ⌮➼ࡢෆᐜ
ὀ㸲㸧
ᐇࡏࡎ
〇㐀ᕤ⛬ࡢᴫせ㸦ࣇ࣮ࣟࢳ࣮ࣕ
ࢺ㸧ὀ㸳㸧ὀ㸴㸧
㸦άཬࡧ㝖ཤฎ⌮ࡣୗ⥺ࢆ
ࡋࠊ᮲௳ࢆලయⓗグ㍕㸧
ูῧ1ཧ↷
࢘ࣝࢫࢡࣜࣛࣥࢫヨ㦂⤖ᯝࡢ
ᴫせὀ㸵㸧 ูῧ2ཧ↷
ὀ㸯㸧 」ᩘࡢ⏕≀⏤᮶ཎᩱཪࡣᮦᩱࢆ⏝ࡋ࡚࠸ࡿሙྜࠊู⣬ᵝᘧ㸰ࡣᙜヱཎᩱཪࡣᮦᩱẖసᡂࡍࡿࠋ ὀ㸰㸧 ື≀✀ࠊ⏝㒊ࡶグ㍕ࡍࡿࠋ
ὀ㸱㸧 ྜ⮴ࡍࡿ࿌♧࣭㏻▱➼ࡀ࠶ࡿሙྜࡣᘬ⏝ࡍࡿࠋ
ὀ㸲㸧 ⏕≀⏤᮶ཎᩱཪࡣᮦᩱࡢ〇㐀ᕤ⛬࠾ࡅࡿࡍ࡚ࡢάฎ⌮➼ࡢෆᐜࢆグ㍕ࡍࡿࠋ࡞࠾ࠊู⣬ࡋ࡚グ
㍕ࡋ࡚ࡶࡼ࠸ࠋ
ὀ㸳㸧 ⁛⳦ᕤ⛬ࡘ࠸࡚ࡣࠊ᪉ἲ࣭᮲௳ࡶྵࡵ࡚グ㍕ࡍࡿࠋ࡞࠾ࠊู⣬ࡋ࡚グ㍕ࡋ࡚ࡶࡼ࠸ࠋࡲࡓࠊ」ᩘࡢ⏕
≀⏤᮶ཎᩱཪࡣᮦᩱࢆ⏝ࡋ࡚࠸ࡿሙྜࡣᮏḍࡣඹ㏻࡞ࡿࡢ࡛ࠊࠕۑۑ㸦ඹ㏻࡞ࡿཎᩱཪࡣᮦᩱ
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1 〇㐀ᕤ⛬ࡢᴫせ㸦ࣇ࣮ࣟࢳ࣮ࣕࢺ㸧 Stage 1๓ᇵ㣴ཬࡧᣑᇵ㣴 Ў
Stage 2
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Ў Stage 4
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Stage 5a
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Ў
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Ў Stage 6
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Ў Stage 7
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Ў Stage 8
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࢘ࣝࢫ㝖ཤࢁ㐣
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⃰⦰ཬࡧ
Ў Stage 11
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ࡋ㸪ホ౯ࡋࡓࠋ≉␗ⓗࣔࢹࣝ࢘ࣝࢫࡋ࡚ࡣ㸪CHO⣽⬊ᰴᏑᅾࡋ࠺ࡿෆᅾᛶࣞࢺࣟ࢘
ࣝࢫྠࡌ⛉ᒓࡍࡿ␗✀ᣦྥᛶ࣐࢘ࢫⓑ⾑࢘ࣝࢫ㸦XMuLV㸧ࢆ㸪㠀≉␗ⓗࣔࢹࣝ࢘ࣝ
ࢫࡋ࡚ࡣ㸪≉ᛶࡢ␗࡞ࡿᵝࠎ࡞࢘ࣝࢫࡋ࡚࣐࢘ࢫ࣐ࢽ࣮ࣗࢺ࢘ࣝࢫ㸦MVM㸧㸪௬ᛶ
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〇㐀ᕤ⛬ࡢ࠺ࡕ࢘ࣝࢫ㝖ཤ㸭ά㛵ࡍࡿ ࢡ࣐ࣟࢺࢢࣛࣇ
࣮㸦Stage 4㸧ᕤ⛬㸪࢘ࣝࢫάཬࡧ 㸦Stage 5a㸧ᕤ⛬㸪㝜࢜ࣥࢡ࣐ࣟࢺࢢࣛࣇ
࣮㸦Stage 8㸧ᕤ⛬ཬࡧ࢘ࣝࢫ㝖ཤࢁ㐣㸦Stage 9㸧ᕤ⛬࠾ࡅࡿ࢘ࣝࢫࢡࣜࣛࣥࢫᣦᩘࢆ
⾲ 1
♧ࡍࠋ࡞࠾㸪࣮࣡ࢫࢺࢣ࣮ࢫ࡛ࡢ࢘ࣝࢫࢡࣜࣛࣥࢫ⬟ࢆホ౯ࡍࡿࡓࡵ㸪 ᐃ⤖ᯝࡢ࠺ࡕ᭱ࡶప࠸್࡛ホ౯ࡋࡓࠋ
⾲ 1 ࢘ࣝࢫࢡࣜࣛࣥࢫᣦᩘ
ᕤ⛬ ࢘ࣝࢫࢡࣜࣛࣥࢫᣦᩘ1)㸦log10㸧
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