?? ??? ??(monoclonal antibody)??

1
???? ??? ???

• ????? ??????
• ??????
• ? ? ?

2
???? ??? ???

• ????? ??
• ????? ??
• ????
• ???? ??
• ??? ????

3
????? ??

• ?? ??? ??(monoclonal antibody)??
• ? ?? ??? ?? ??? ?????? ???? ??
• ???, ?? ???, ??? ???

4
(No Transcript)
5
????? ??? ????
6
B??? ?? ??
DR
sIg
CD20
CD19
CD22
Figure reprinted from Seminars in Oncology, Vol.
26 Press OW. Radiolabeled antibody therapy of
B-cell lymphoma. (Suppl 14)58-65, 1999, with
permission from Elsevier.
7
?? ?? ???? ????? ??
???? ??????? ??
CD19 B4 B4(Ricin)
CD20 ???? (???) 131I(??) 90Y(???)
CD22 ?????? BL-22
CD52 ?????
1D10 HLA DR ?????
Lym-1 131 I 67Copper
Tac ???? LMB-2
8
????(Rituximab,MabThera)
Chimeric anti-human CD20 ?? ??? ??
VH
Murine variable regions
C?1
VL
Human constant ? region
C?
Human constant Fc region
Variable region murine IgG1 kappa
anti-CD20 Constant region human IgG1 heavy chain
and kappa light chain
9
???? (Rituximab)

• ???? ??? ???
• ?????? ????
• ???? R-CHOP, R-CVP
• ???? RICE, RDHAP
• ??????? ??
• ????
• ????
• CD20 ??? ?? ??? ????? ??? ????,???? ? ?? ?? ?

10
??? ? B?? ???, 60???5-year Update of the GELA
Study
Overall Survival
1.0
0.8
0.6
0.4
0.2
0.0
0.0
Years
11
?? ???
93
1.0
R-CHEMO (n413)
0.9
p 0.0001
84
0.8
CHEMO (n410)
0.7
0.6
Probability
0.5
0.4
0.3
??? ? B?? ???, 60???
0.2
0.1
0.0
0
10
20
30
40
50
60
M o n t h s
Pfreundschuh et al., Lancet Oncology 2006
12
????-HyperCVAD ? ????-CHOP, ???????(MCL)

• R-CHOP-like ?? R-HyperCVAD ? ????????? ??

Outcome R-CHOP-like, R-HyperCVAD,
1-yr PFS 76 97
3-yr PFS 55 78
1-yr OS 94 97
3-yr OS 68 97
Vose J, et al. ASCO 2006. Abstract 7511.
13
?????(Alemtuzumab, Campath)

• ? CD52 ?? ??? ??
• ???, ??? ?????? ???
• ??? ????? ???? ??
• ?? ??? T ?? ???? ???
• ????
• ?????? ????? ?? ?? ??

14
??????(radioimmunotherapy)

• ???(Zevalin 90Y ibritumomab tiuxetan)
• ??(Bexxar 131I tositumomab)

15
?????? ?? ??? ?????

• ?? ??? ??
• ??? ??
• ??? ??
• ???? ??

???1
???????1
???2
Radio-immunotherapy
?
???????2
????
????
Horning. Semin Oncol 200330(suppl 17)2934
16
?? ?? ?????
??????
17
???(Zevalin 90Y ibritumomab tiuxetan)
18
??????? ??
Naked antibody

• ??? ??? ??? ??? ?? ???
• ???? ???? ????? ??
• ??? ???? ?? ??? ???? ??

Zevalin
90Y
90Y
90Y
Press. Semin Hematol 200037(suppl 7)28Krasner
Joyce. Curr Pharma Biotech 20012341349Zelene
tz. Curr Opin Oncol 199911375380
19
???(Zevalin 90Y ibritumomab tiuxetan)

• 90Y 131I
• ??? No Yes
• ???? (MeV) 2.3 0.6
• ??? (?) 2.7 8.0
• ?? (mm)
• ?90 5.3 0.8
• ?? 11.0 2.9 ?? 2.5 0.4

20
Tumour Response with Zevalin
FDG PET Scans
Before
After
21
??? ? ????, ??? ???
At Week 13 after beginning treatment
100
Partial response
90
80
P0.002
80
Complete response
70
56
60
Patients ()
50
40
30
30
20
16
P0.04
10
n73
n70
0

Zevalin
Rituximab
International Workshop for NHL Response
Criteria(IWRC)
Witzig et al. J Clin Oncol 20022024532463
22
??? ???? ??? ??
???
?? ??
Plt0.001
6.5
6.4
74
67
4.0
32
15CR
n54
n51
n34
n54
n17
n17

Witzig et al. J Clin Oncol 20022032623269Brief
ing document. IDEC Pharm Corp 2001
23
???? ?? ??, ??? ???
?? ??
???
20
100
1 prior therapy (n53)
1 prior therapy (n53)
90.6
?2 prior therapies (n116)
?2 prior therapies (n116)
90
79.3
80
14.9
14.2
15
70
54.7
60
Patients ()
Months
9.2
50
10
8.2
40
30.2
30
5
20
10
0
0
ORR
CR/CRu
TTP
DR
Emmanouilides et al. Blood 2003102306b-307b,
abstract 4949
24
??? ???? ????

• ?? ??, ??? ???
• ?? ?? ? ????, ??? ???
• ???, ??? , ??? ? B?? ???
• ???, ???, ???? ???
• ?? ???????

25
?? ??

• ??????(Flavopiridol)
• ??????(Depsipetide)
• ?????? 1(Bryostatin 1)
• UCN-01
• ????(Velcade, bortezomib)
• ????(Genasense)

26
Survival Prediction
Poor
Poor
Favorable
Favorable
Favorable
27
??????(Flavopiridol)

• ???? D1, CDK1,2,4 ???
• ??? ?? ??? ???? ???
• ??? 11
• ?? ?? ????
• ??????/?????/????
• ??????/????

28
??????(Depsipetide)

• DNA ??? ?????? ???
• ?? ?? ????
• ??????/?????/????-?? ???
• ??????-?? T?? ???
• ??????-T?? ???

29
??????, ?? T ?? ???

• ??? 27
• ??? 37

Response Outcomes With Depsipeptide
Percentage of Patients
Piekarz RL, et al. ASH 2005. Abstract 231.
30
?????? 1(Bryostatin 1)

• PKC ???
• ??????/?????
• ? 1 ? ?? ??? 21
• ??????
• ?? ?? 1/14
• ??????-?? ???, ?????? ???
• ??? 12
• ?? ?? ????
• ??????/???? ???, ?? ???? ???
• ??????/????? ?? ? ??? ???

31
UCN-01

• PKC ???
• ? 1 ? ????
• 1?? ALCL?? 2? ? ??? ????
• ?? ?? ?? ??
• UCN-01-T ?? ???

32
????(Velcade, bortezomib)

• ????? ???
• ??? ??? ??? 2? ??
• ???? ???? ??? ???? ??
• ????
• ?? ??? ???? ?? ???? ???? ?? ?

33
????/??????? ??? ???
Bortezomib 1.3 mg/m2 twice weekly Days 1, 4, 8,
and 11 of 21-day cycle for up to 5 cycles
Rituximab 375 mg/m2/wk for first 4 wks (n 41)
Phase II study relapsed/refractory follicular
lymphoma or marginal zone NHL (N 81)
Week 15
Bortezomib 1.6 mg/m2/wk Days 1, 8, 15, and 22 of
35-day cycle for up to 3 cycles Rituximab 375
mg/m2/wk for first 4 wks (n 40)
Response, Twice-Weekly Bortezomib Rituximab(n 35) Once-Weekly Bortezomib Rituximab(n 39)
Overall response CR/CRu PR 51 12 40 54 13 41
Stable disease 31 33
Progressive disease 17 13
Grade 3/4 toxicity 54 18
de Vos S, et al. ASH 2005. Abstract 17.
34
????/R-CHOP

• ? ½?
• ??? 20
• ?????? (n 15)
• 4?? ???? (n 7)

Response Patients, n () (N 20)
CR 9 (45)
CRu 8 (40)
PR 2 (10)
Objective response 19 (95)
Leonard JP, et al. ASH 2005. Abstract 491.
35
????(Genasense)
36
????(Genasense)

• BCL-2 ??
• ?? ?? ????
• ????/????-??? ???

37
????? ??

• 20?? ?? ?? ???? ???? ?? ??
• 18?? ???? ?? ?? ??
• 8/11 ???? (73) PCR ???? ??
• ?? ??? ????? ? 3 ? ?? ???

Bendandi et al. Nat Med. 199951171-1177.
38
??? ??????

• ??? ???? ?? ??, ??? ????? ????
• R-CHOP 14
• ????
• ?????
• ??????

39
??? ??????

• R-GIFOX
• ???, ??? ???
• ??? 77
• ViGePP
• ???, ??? ???
• ???? 23
• CHOP-EG
• T?? ???
• ???? 61.5

40
???? ??? ???

• ????? ??
• ????? ??
• ????
• ???? ??
• ??? ????

41
? ?

• ??? ??? ??? ??? ??? ??? ?? ?? ?? ??? ??? ???
  ????? ?? ?? ??? ?? ??? ??? ???? ???? ???? ??? ???
  ????.