Transcription of 成人T細胞白血病リンパ腫に対する抗体療法 （抗 CCR4抗体）
1 1 T CCR4 CCR4 (ATL) - 2010 2006 2010 CCR4 2 ATL T (ATL) ATL . ATL ( Tobinai et al, Abeloff s Clinical Oncology (ed 4) 2008:2425 ATL (2ndline )( ) (1stline )ATL MST 160% (0/4)CPT 1138% (5/13)2 Deoxycoformycin 32% (10/31*)Cladribine7% (1/15)* ATL Tsukasaki et al, J Clin Oncol 2007;25:5458 Ichihashi et al, Oncology 1992;49:333 Tsuda et al, Br J Cancer 1994;70:771 Tobinai et al, Jpn J Clin 1992;22:164 Tobinai et al, Int J Hematol 2003.)
2 77:5123 CCR4 CCR4 (KW 0761) KM2160 Imai et al, Int Immunol, 1999KM2760 Niwa et al, Cancer Res, 2004KW 0761 Ishii et al, Clin Cancer Res, 2010 Yamamoto et al, J Clin Oncol, 2010 Asn297 Asn297 Fucose ADCC Shinkawa et al, JBC 2003 CCR4 KW 0761 KW 0761 Extracellular regionsN terminalCCR4(CCchemokinereceptor4)Fucose AsnAsn297297 Fc ADCC POTELLIGENT CCR4 (CC chemokine receptor 4)ATL 90% ATL 4 2006 2008)KW 0761 ATL/PTCL 1 D1 8 15 22 ATL / PTCL(CCR4+)N=16 CohortDose(mg/kg)No.
3 Of pts(ATL)10013(2)No. of ptsORR(%)ALL CR (2) (4) (3) (2)Expanded (2)ATL/PTCL162331 ATL13 2231 2 : mg/kgYamamoto et al, J Clin Oncol 2010 ;28:1519 Hematological CR !! 10,000(/ L)KW 0761 ( mg/kg ) 103 68 5,000 (/ )01 22229365043158 ATL days5KW 0761 ( mg/kg ) 102 60 1 4 3 SD CR 401: 64 T (PTCL NOS)Hematological CR 3,0004,0005,000l counts 3) KW 0761 ( mg/kg ) 01,0002,0003,00018 15 22 29 36 43 50 DaysPeripheral cel( / mm3 (PTCL PTCL Day50 Day 5 Day1 Day50LN: < 25%.)
4 6101102MM4660MF tumor stageATLacute44 PDSDSD PDSD CR291002+ # ofinfusionPB Skin LNORPFS(days)Response CCR4 1 1(0 01)102103201202203204301302303 MFMFMFMMF606855666657606469 ATL acuteATL acuteATL acuteATL acuteATL acuteATL acuteATL acuteATL acuteATL lymphoma444414444 CRCRPR CR SD PR CRPD CRSDSDSD PDSDSD CRPRSDSDPDCRPDPDPD100285503681071+362929 ( )2( )3( )401402403411412413 FFFMMF646264556258 PTCL NOSATL acuteATL lymphomaATL acuteATL acutePTCL NOS444444 CRCR CR CRCR PD PRPRSD SDPRPRSDPDCRSD812+644328714590+4( )Ex panted( ) ; (5/16; 2 CRs & 3 PRs) ; (7/16 )(Aug.)
5 , 2010 ) 7 2009 2010 ) ATLKW 076110/k /d(i ) CCR4 CCR4 2 (design #1) ATL mg/kg/day (iv) weekly x 8 FCM / IHCFCM / IHC CCR4 KW 0761, mg/kg D1 8 15 22 29 36 43 50 1 mos2 mos1 mos * (n=27) CTCAE 1 434 1 434 **10 2491126 50178018 GTP 304 10 4 Ca 203 50178018 ALT 20113214 AST 20105014 305108 Ca 013 **10 1 10 1 10 1 / (LDH )0314* ** Stevens Johnson ** 8 13CR**0PR0SD0PD0NE(%) (100 %) 13n * (n=26**) PR[95% CI]13 8335202041125010 / ()(63 %) 268125[25 92)(25 %)3[6 57](50 %)13[30 70]* Tsukasaki et al.]
6 (J Clin Oncol 2009;27:453)** 1 ** CRu (95% 5% : (ORR) 50% (95%CI 30 70) (P206); 55 , KW 0761 (cells/ L) CD4CD25400060008000 020000 1428425670 Time (days) (ATT ) ATL SSC HCCR49 (P206); 55 Day 6 Day 57 : mg/kgKW 0761 ( )(P206); 55 Day 57, Grade 1 Day 190, Grade 1 Day 141, Grade 2 (day57): , , HECD8 HE10 (P213); 69 mg/kgKW 0761 Day 5 Day 63 : (CRu)CCR4 2.)
7 2, 2010 ATL 27 26 KW 0761: 1. 0 mg/kg)27 50% (13/26; 95% CI, 30 70%) : 8 5 (PFS) : 5 / (ALT, AST ) 11 mLSG15(VCAP/AMP/VECP)x4cyclesCCR4+ ID:NCT01173887 ATL 1stline ATL( 20yo) x 4 cyclesmLSG15 x 4 cycles+KW 0761(Bi weekly x 8)CCR4 CCR4 : (CR )CCR4+(n=44)Cli i lT i lIDNCT01192984T/NK T/NK ( 20 yo)KW mg/kg/day (iv) weekly x 8 CCR4 CCR4 CCR4+(n=35) ID:NCT01192984T/NK (CTCL ).
8 (ORR) (KW 0761)(2009 2010 ) / KW 0761 (2009 2010 ) CCR4 (KW 0761)(2006 2008)CCR4 Cancer Immunol Immunother, 2009 2010 ADCC CCR4 CCR4 in vitro ATL ADCCClin Cancer Res, 2005 Clin Cancer Res, 2004bCCR4 Treg CCR4 Cancer Res, 2006 Int J Cancer, 2007 Cancer Sci, 2006 J Clin Oncol, 2009J Immunol, 2009 CCR4; ATL Clin Cancer Res, 2003 CCR4; T Clin Cancer Res, 2004aADCC CCR4 Cancer Res, 2004 Br J Haematol 2008 Clin Cancer Res 2007 Leukemia2006 ATL LNCCR4 staining2000 CCR4 199912 1 2 2 17 FCM CCR4 T *(2011 )
9 * * CCR4 T (mLSG15) T/NK CTCL ) Phase II 13 CCR4 KW-0761 200132 3926153 6989145 7666418 1270595 CDR 4052515 7504104 7842797 1449850
