CONFIDENTIAL

KW-0761

2 2 : CTD

2.5

KW-0761 2.5

CONFIDENTIAL - 2 -

ADCC Antibody-dependent cellular cytotoxicity ATL Adult T-cell leukemia-lymphoma T AZT Azidothymidine B-NHL B-cell non-Hodgkin lymphoma B BUN Blood urea nitrogen CDC Complement-dependent cytotoxicity CDR Complementarity determining region CR Complete response/Complete remission CRu Uncertain complete response/Uncertain complete remissionCTCAE Common terminology criteria for adverse events CTCL Cutaneous T-cell lymphoma T div Drip intravenous injection DLT Dose-limiting toxicity FCM Flow cytometry G-CSF Granulocyte-colony stimulating factor HAM/TSP HTLV-1-associated myelopathy/tropical spastic paraparesis HTLV-1

/ HDAC Histone deacetylase HU HTLV-1 uveitis HTLV-1 HBc Hepatitis B core B HBs Hepatitis B surface B HTLV-1

HTLV-I Human T-lymphotropic virus type 1 T 1

IFN Interferon IgG Immunoglobulin G G IHC Immunohistochemistry IL Interleukin iv Intravenous injection JCOG Japan Clinical Oncology Group LDH Lactate dehydrogenase LSG Lymphoma Study Group LVEF Left ventricular ejection fraction MF Mycosis fungoides MST Median survival time MTD Maximum tolerated dose MTX Methotrexate NHL Non-Hodgkin lymphoma NK Natural killer NOAEL No observed adverse effect level OS Overall survival PaO2 Arterial partial oxygen pressure PD Progressive disease PDN Prednisone PFS Progression free survival PNP Purine-nucleoside phosphorylase

KW-0761 2.5

CONFIDENTIAL - 3 -

po Latin per os Oral administration PR Partial response/Partial remission PS Performance status PTCL Peripheral T-cell lymphoma T PTCL-NOS Peripheral T-cell lymphoma, not otherwise specified T -

SAR Seasonal allergic rhinitis SaO2 Arterial oxygen saturation SD Stable disease SpO2 Oxygen saturation by pulse oximetry ST Sulfamethoxazole Trimethoprim

WHO World Health Organization

Ara-C/MTX/PDN Ara-C Cytarabine MTX Methotrexate PDN Prednisone

AUC

AUC0- AUC0-t t t

AZT/IFN AZT Azidothymidine IFN Interferon

CCR4 CC chemokine receptor 4 ChemokineCC CXC C CX3C 4

CCR4 CC chemokine TARC Thymus and activation-regulated chemokine MDC Macrophage-derived chemokine

CD4 T II

CD8 T I

CD20 B B CD25 IL-2

CHOP

C Cyclophosphamide Hydrate H Doxorubicin Hydrochloride O Vincristine Sulfate P Prednisone

CL Cmax Ctrough ELISA Fc IgG C

Foxp3 T ATL

HBV-DNA B - DNA IL-4 -4 B T

KW-0761 2.5

CONFIDENTIAL - 4 -

NK Natural killer T

IL-5 -5 B T IL-13 -13

LSG15

VCAP+AMP+VECP VCAP Vincristine Sulfate Cyclophosphamide Hydrate Doxorubicin

Hydrochloride Prednisone AMP Doxorubicin Hydrochloride Ranimustine Prednisone VECP Vindesine Sulfate Etoposide Carboplatin Prednisone

LSG19 Biweekly CHOP CHOP 2 Lyn Src mLSG15 VCAP/AMP/VECP+Ara-C/MTX/PDN mLSG19 Biweekly CHOP/MTX/PDN Peg-IFN Peginterferon QT Q T QTc QT Syk Spleen tyrosine kinase t1/2 t1/2 Th2 IL-4 IL-5 IL-10 IL-13

T Vss

KW-0761 2.5

CONFIDENTIAL - 5 -

........................................................................................................2

............................................................................................................................................5 2.5 ................................................................................ 6 2.5.1 ........................................................................................................................ 6 2.5.2 .............................................................................................. 17 2.5.3 .................................................................................................. 17 2.5.4 .................................................................................................................. 22 2.5.5 .................................................................................................................. 26 2.5.6 .................................................................................. 36 2.5.7 .................................................................................................................................. 41

KW-0761 2.5

CONFIDENTIAL - 6 -

2.5

2.5.1

2.5.1.1 KW-0761 KW-0761 CCR4 219

2 499 2 G IgG 1Fc

ADCC ADCCPOTELLIGENT®

CDC ADCC

2005 CCR4 T ATL2006 6 I 0761-0501 2009 5 II

0761-002 2010 8 CCR4 ATL22 232

3 HTLV

2008 12 8 T ATL1)

2.5.1.2 ATL

2.5.1.2.1 2,3) 1977 T ATL

1980 ATLT 1 HTLV-1 ATL

HTLV-1 DNAT

HTLV-1 HTLV-1 ATL HTLV-1 2 5% ATL

ATL HTLV-1 HTLV-1 /HAM/TSP HTLV-1 HU ATL 19801990 4-9) HTLV-1 120

700 ATL 58 6140 93 98% ATL

2009 201010,11) ATL

67 56 80.8%HTLV-1 108

20 120 11150

KW-0761 2.5

CONFIDENTIAL - 7 -

20109 HTLV-1

HTLV-1

2.5.1.2.2 2,3) ATL i

ii iiiT 3ATL 3761 1988 1997 72%

29% 20% 27% 29% 9) 1984 1987 ATL 854

2.5.1.2.2-112)

• 4000/ L 5%Lactate dehydrogenase LDH 1.5

5% • 4000/ L T 3500/ L

LDH 25%

• 4000/ L 1%

• 3 ATL

KW-0761 2.5

CONFIDENTIAL - 8 -

2.5.1.2.2-1 LSG

HTLV-1 + + + + / L 4000 4000a 4000

T 5% +b 1% +b T No + LDH 1.5N 2N

Ca mEq/L 5.5 5.5 No +

No Yes

No No

No No No No

No No No No

No No N

5%

a T 3500/ L b 5%

2010 11) 2006 2007 ATL910 46.7% 34.8% 10.3%8.2%

2.5.1.3 ATL ATL PS LDH 40

LDHBUN

ATLATL

BCHOP

ATL

13,14) ATLKW-0761 ATL

OS GillATL 7 19 ATL AZT/IFN3

KW-0761 2.5

CONFIDENTIAL - 9 -

15) Hermine ATL 19 AZT/IFN6 6 16) ATL 7

IFN 57% 1.517) ATL

2007 13 HTLV 2007

ATL 20092.5.1.3-1 ATL

18-20)

2.5.1.3-1 ATL

ATL • • AZT/IFN Watch and Wait

• Watch and Wait

ATL • •

• biweekly-CHOP III

VCAP/AMP/VECP AZT/IFN

•

• AZT/IFN

ATL • • VCAP/AMP/VECP •

• •

• Up-front • + IFN- +

• Peg-IFN AZT II

• + IFN- PNP

HDACSurvivin - Syk Lyn

•

KW-0761 2.5

CONFIDENTIAL - 10 -

VCR : Vincristine CPA : Cyclophosphamide ADM : Doxorubicin PDN : Prednisone MCNU : Ranimustine VDS : Vindesine ETP : Etoposide CBDCA : Carboplatin

ATL

2.5.1.3.1 JCOG LSG JCOG930321) LSG15

2.5.1.3.1-1 a b c 4 1 7MTX 15 mg PDN 10 mg 1 3 5

JCOG9303ATL 93 80.6% 75/93

35.5% 33/9319.6% 11/56 66.7% 18/27

40.0% 4/10 MST 13 231.3%

a VCAP b AMP

VCR 1 mg/m2, iv day 1 ADM 30 mg/m2, div day 8 CPA 350 mg/m2, div day 1 MCNU 60 mg/m2, div day 8 ADM 40 mg/m2, div day 1 PDN 40 mg/m2, po day 8 PDN 40 mg/m2, po day 1

c VECP VDS 2.4 mg/m2, iv day 15 ETP 100 mg/m2, div day 15-17 CBDCA 250 mg/m2, div day 15 PDN 40 mg/m2, po day 15-17

2.5.1.3.1-1 LSG15

JCOG LSG JCOG980122) LSG15 mLSG15 modified

LSG15 LSG19 Biweekly CHOPmLSG15 LSG15 a b c 4

1 6 MTX 15 mg Ara-C 40 mg PDN 10 mg1 3 5 JCOG9801

NHL LSG19mLSG15 mLSG19 mLSG15

ATL118 mLSG15 72% mLSG19 66%

40% 25% 324% 13% MST 12.7 10.9

mLSG15 mLSG19 Grade 498% 83% 74% 17% 7% 3%

mLSG15 3ATL mLSG15 mLSG19

KW-0761 2.5

CONFIDENTIAL - 11 -

56 56 56mLSG15 mLSG19 mLSG15

2.5.1.3.2 ATL

ATL 40 345.3% 33.8% 23) 5 21

16 76%67 ATL

2 33.3% 1524)

2.5.1.3.3 AZT/IFN 2011 4 2007 13 HTLV

IFN - AZTHTLV-1 ATL 209

100 AZT/IFN 66% MST 24 550% AZT/IFN

MST 7 5 20%JCOG9801 mLSG15

Indolent type AZT/IFN

2.5.1.3.4 ATL

1994 4 1994 4 2.5.1.3.4-1

23.5% 4/17 33.3% 1/325.0% 5/20 25,26) 2.5.1.3.4-2

46.2% 6/1325.0% 2/8 38.1% 8/21

17 10 27)

KW-0761 2.5

CONFIDENTIAL - 12 -

2.5.1.3.4-1 4 5 mg/m2/week iv 4

23.5% 4/17

33.3% 1/3 33.3% 2/6

75.0% 3/4 ATL

33.3% 10/30

2.5.1.3.4-2

800 2800 mg/day po 7 1 2 3

* 46.2% 6/13 1/13

25.0% 2/8 0/8 100.0% 2/2 1/2

ATL

43.5% 10/23 2/23 *

2.5.1.4 ATL KW-0761 WHO ATL NHL

28-30) NHL ATL31) ATL NHL

JCOG LSGATL 32-35) 2011 4 ATL

mLSG15 MST 12.7 3 24% 22)

ATL 12 56

80.8%

ATL ATL NHL B CD20

RituximabCHOP

36,37) B 38,39)

BATL T

ATL 88.3% CCR4 CCR4

KW-0761 2.5

CONFIDENTIAL - 13 -

40) CCR4 TCTCL T 41)

IL -4 IL-5 IL-13CD4 II T Th2 42)

T CCR4 43) CCR4KW-0761 Fc

ADCC POTELLIGENT® 44)

CDCADCC

ATLKW-0761 ATL

Autologous in vitro 45)

CCR4 Th2 46) KW-0761 Th2 in vitro

CCR4 47,48)

KW-0761 ATL

2.5.1.5 ATL KW-0761 20

ATLATL 700 1000

560 800

2 448 6406 268 384

4268 384 1/3 89 128

ATL20

KW-0761 2.5

CONFIDENTIAL - 14 -

1

2

3 infusion reaction pre-medication

infusion reactionpre-medication pre-medication

Pre-medication

4 0.01 mg/kg 4

40 mg/kg 1/40008 4

1 2

3pre-medication Pre-medication acute infusion reactionKW-0761 30 1 30 50 mg d-

1 2 mg 1 300500 mg

KW-0761 30 60 4 20

20 13

I 0761-0501 CCR4 ATL CTCLT PTCL II

KW-0761 0.01 0.1 0.5 1.0 mg/kgATL

1 ATL4

B1 4 4

1 2 7.18 16.5

I ATL KW-0761ATL II II

1

KW-0761 2.5

CONFIDENTIAL - 15 -

2

20

1

ATL

2

3 I CCR4

CCR4CCR4

1 ATL II ATLII

202010 7 mLSG15 KW-0761 II

0761-003 20 2

3 CCR4

II 0761-002 CCR4 ATL 1.0 mg/kg KW-0761 1 8

0761-002 0761-0501 4KW-0761

ATL KW-0761B

4 8

KW-0761 2.5

CONFIDENTIAL - 16 -

I II

CCR4 T

1 1 mg/kg 1

8

2010 8CCR4 T 22 232

ATL

ATLmLSG15 KW-0761 0761-003 20

ATL CCR4 T/NK

202010 7 II 0761-004 20

SAR I

0761-EU-0015.3.3.1-1 PTCL/CTCL

KW-0761-001 KW-0761-002 2010 125.3.5.4-2

2.5.1.6 2.5.1.6-1

KW-0761 2.5

CONFIDENTIAL - 17 -

2.5.1.6-1

I0761-0501 (5.3.5.2-15.3.5.2-4)

CCR4

ATLCCR4

MFPTCL

0.01 0.1 0.5 1.0 mg/kg 14 3 6

ATL 13

1 PTCL 3

4

II0761-002 (5.3.5.2-9)

CCR4

ATL

1.0 mg/kg 1 8

27

1

8

I0761-EU-001 ( 5.3.3.1-1)

SAR

0.0001 0.0003 0.0010.003 mg/kg SAR

mg/kg

725

SAR5

18

2.5.2

KW-0761 KW-0761 ELISA

KW-0761

2.5.3

2.5.3.1 in vitro KW-0761

KW-0761 149000 IgG1

50)

2.5.3.2 0.0001 0.0003 0.001 0.003 mg/kg KW-0761

0.0001 0.0003 mg/kg KW-0761

10 ng/mL 0.001 0.003 mg/kg KW-0761 2.5.3.2-1 2.5.3.2-1 0.003 mg/kg

KW-0761 2.5

CONFIDENTIAL - 18 -

KW-0761 Cmax 0.001 mg/kg 2.922.7.2.2.2.1

2.5.3.2-1 KW-0761 KW-0761 + n=6 7

2.5.3.2-1 KW-0761±

(mg/kg)

Cmax

(ng/mL) AUC0-t

(ng·h/mL) AUC0-

(ng·h/mL) t1/2 (h)

0.001 7 20.3±4.08 505±328

0.003 6 59.2±10.2 5352±1852 8649±2194 144±29.2

2.5.3.3 CCR4 ATL CCR4 PTCL KW-0761 0.01 0.1 0.5

1.0 mg/kg 1 4 KW-07612.5.3.3-1 2.5.3.3-1 4Cmax 1.39 1.95 AUC0-7 days 2.15 3.48

2.5.3.3-2 CL 0.1 mg/kgVss

2.7.2.2.3.1 CCR4 ATL KW-0761 1.0 mg/kg 1 8

KW-0761 2.5.3.3-2 2.5.3.3-38 t1/2 422±147 ± IgG121 8 Cmax Ctrough

40993.2 ng/mL 29546.4 ng/mL Cmax Ctrough

KW-0761 2.5

CONFIDENTIAL - 19 -

KW-07612.7.2.2.3.2

2.5.3.3-1 KW-0761 1 4 KW-0761 + n=1 6

2.5.3.3-1 KW-0761 1 4±

mg/kg

Cmax ng/mL

Ctrough ng/mL

AUC0-7 days ng·h/mL

t1/2 h

206.0±23.1 41.0±39.0 14858±7665 80±52 4 350.0±47.8 a) 158.2±7.4 a) 36586±2987 a) 179±40 a)

0.01 n=3

1.63 (1.38-1.87) a) 2.11 b) 3.42 (1.76-5.08) a) 1831.7±334.1 254.9±447.4 87565±93652 74±85 c)

4 2806.7±1664.5 c) 1515.2±1873.4 c) 327609±322298 c) 201±196 c) 0.1 n=4

1.39 (0.96-2.13) c) 13.65 (3.97-29.40) c) 3.48 (2.03-5.24) c) 8353.2±1993.4 2985.0±605.8 761919±130770 141±23 a)

4 15181.2±872.0 6824.7±872.9 1625609±142277 332±122 0.5 n=3

1.89 (1.52-2.42) 2.32 (2.09-2.75) 2.15 (1.97-2.34) 21758.0±3495.4 7544.2±3008.8 1901206±466590

4 40428.4±5350.8 d) 19516.8±4264.7 d) 4190238±544757 d) 462±51 d) 1.0 n=6

1.95 (1.61-2.09) d) 3.53 (2.19-7.58) d) 2.43 (2.24-2.78) d) -

: a) n=2 b) n=1 c) n=3 d) n=5

2.5.3.3-2 KW-0761 1 4±

mg/kg CL mL/h/kg Vss mL/kg 0.01 3 0.240±0.016 107.5±49.1 0.1 3 0.708±0.646 111.8±41.4 0.5 3 0.237±0.050 115.8±31.0 1.0 6 0.144±0.032 102.7±20.3

KW-0761 2.5

CONFIDENTIAL - 20 -

2.5.3.3-2 KW-0761 1.0 mg/kg 1 8KW-0761 + n=3 27

2.5.3.3-3 KW-0761 1.0 mg/kg 1 8±

Cmax (ng/mL)

Ctrough (ng/mL)

AUC0-7days (ng·h/mL)

t1/2 (h)

16622.0±3324.0 (27) 5151.9±3713.6 (19) 1427204±571447 (19) 124±92 (23) 8 42943.2±14239.5 (5) 33638.3±10572.2 (4) 6297408±1812467 (4) 422±147 (5)

2.25 (1.74-3.09, 5) 3.56 (3.24-3.86, 3) 2.87 (2.50-3.12, 3)

- , :

2.5.3.4 CCR4 ATL CCR4 PTCL KW-0761 0.01 0.1 0.5

1.0 mg/kg 1 4 Cmax AUC0-7 days

0.01 1.0 mg/kg 2.7.2.3.1

2.5.3.5 CCR4 ATL CCR4 PTCL KW-0761 1.0 mg/kg

Cmax AUC0-7 days 2.5.3.5-12.7.2.3.4

KW-0761 2.5

CONFIDENTIAL - 21 -

0

20000

40000

60000

80000C

max

(ng/

mL)

0

2000000

4000000

6000000

8000000

10000000

AU

C0-

7 da

ys (n

g/m

L)

2.5.3.5-1 KW-0761 1.0 mg/kg

2.5.3.6 CCR4 ATL CCR4 PTCL KW-0761 1.0 mg/kg

Cmax AUC0-7 days 2.5.3.6-165 65 74 75

2.7.2.3.5

0

20000

40000

60000

80000

Cm

ax (n

g/m

L)

0

2000000

4000000

6000000

8000000

10000000

AU

C0-

7 da

ys (n

g/m

L)

2.5.3.6-1 KW-0761 1.0 mg/kg

KW-0761 2.5

CONFIDENTIAL - 22 -

2.5.3.7 KW-0761 CCR4 ATL CCR4 PTCL 43 KW-0761

2 KW-0761 KW-07615.0 ng/mL 2.7.2.4.1.1

32 SAR 23 KW-0761KW-0761 0.0003 mg/kg

1 57 KW-0761KW-0761 KW-0761

0.003 mg/kg 129 KW-0761 57 5

10 7.5 ng/mLKW-0761 15 22 5.0

ng/mL 2KW-0761 7.5 ng/mL 2.7.2.4.1.2

2.5.4 I 0761-0501 CCR4

ATL MF PTCL II 0761-002CCR4 ATLATL 0761-0501 PTCL

2.5.4.1

2.5.4.1.1 0761-0501 0761-002 2006 6

20 2009 5 20 0761-0501 KW-0761 0.01 0.1 0.5 1.0 mg/kg 1 4

KW-0761DLT MTD KW-0761

PFS 0761-002 KW-0761 1.0 mg/kg 1 8

KW-0761

PFS OS 2.7.3.1.1 2.7.3.2

2.5.4.1.2 0761-0501 0761-002 HTLV-I LSG

12)

ATL CCR4KW-0761

1CCR4

KW-0761 2.5

CONFIDENTIAL - 23 -

FCM CCR4IHC 2.7.1.1.2 0761-002 CCR4

44 CCR4 100.0% 44/442.7.3.3.1.2

2.7.3.3.1.1

2.5.4.1.3 0761-0501 0761-002

PS ATL0761-0501 16 ATL 13 0761-002

26 0761-0501 62.0 55 69 0761-002 64.5

49 83 0761-002 65ATL 67

11)

PS 0761-0501 0 7 1 6 0761-002 2

0 15 1 6 2 5 ATL2.7.3.3.1.3

2.5.4.2

2.5.4.2.1 0761-0501 0761-002

PFS 0761-002 OS KW-0761

ATL

0761-0501 0761-002

0761-0501 0761-002

peer review 0761-05010761-002

PFSOS

ATL 0761-0501

51,52)

53) CTCL 54)

KW-0761 2.5

CONFIDENTIAL - 24 -

0761-002 13 ATL19)

2.7.3.1.2

2.5.4.2.2 0761-0501 ATL CR 2 PR 2

30.8% 4/13 0761-002 ATL CR 8 PR 5

50.0% 13/26 95% 29.9 70.1% 95% 29.9%5% CCR4

ATL KW-0761 0761-002 6565 38.5% 5/13 61.5% 8/13

2.7.3.3.2.1 2.7.3.3.3

2.5.4.2.2.1 0761-0501 0761-002 100% 0761-0501

CR 5 +PR /6 0761-002 CR 13 /13 0761-0021 2

0761-0501 0761-002 25.0% CR 1 +PR 2 /12 38.1% CR 3 +PR 5 /21

0761-0501 0761-00225.0% CR 2 /8 25.0% CR 2 + CRu 1 /12

0761-0501 0761-00250.0% CR 2 +PR 1 /6 62.5% CR 3 +PR 2 /8 2.7.3.3.2.1

2.5.4.2.3 PFS OS Kaplan-Meier PFS 50% 0761-0501 0761-002

54 158 0761-002 Kaplan-Meier OS50% 50% 2.7.3.3.2.22.7.3.3.2.3

2.5.4.2.4 KW-0761 0761-0501 0761-002 KW-0761

KW-0761 2.7.3.3.4

1 0761-0501 CCR4

PR PR 2 1 001*

0.01 mg/kg KW-0761 2

*新薬承認情報提供時に置き換え

KW-0761 2.5

CONFIDENTIAL - 25 -

NE

2 0761-002 CCR4

PR CR 6 1 1.0 mg/kg KW-0761 4

PR PR6 6

CCR4 1

2.5.4.3 0761-0501 0.01 0.1 0.5 1.0 mg/kg 1 4 DLT

0.01 mg/kg MTD1.0 mg/kg 3 1 DLT

1.0 mg/kg DLT 6 1 1.0 mg/kg 0761-0021.0 mg/kg 1.0 mg/kg 4

IgG1KW-0761 ATL in vitro

ATL 0.1 10 g/mLKW-0761 ADCC 0761-0501

0.01 1.0 mg/kg Ctrough 0.041 7.54 g/mL 4Ctrough 0.16 19.5 g/mL Ctrough in vitro 0.1 10

g/mL ADCCKW-0761

KW-0761

4

ATL KW-07610761-002 4

8 0761-002 1.0 mg/kg 1 8 CCR4

ATL 50.0% 95% 29.970.1% 95% 29.9% 5%

ATL KW-0761 8

KW-0761 82.7.3.4

*新薬承認情報提供時に置き換え

KW-0761 2.5

CONFIDENTIAL - 26 -

2.5.4.4 0761-002 CR 8 PR 5 50.0% 13/26

95% 29.9 70.1% 95% 29.9% 5%ATL 1

ATL

65KW-0761

0761-002 8 1KW-0761

KW-0761 CCR4 ATLKW-0761

1 1 mg/kg 18

2.5.5

2.5.5.1 CCR4 ATL CCR4 MF

PTCL I 0761-0501 CCR4 ATLII 0761-002

2 PTCL/CTCL I/II

KW-0761-001 KW-0761-001PTCL/CTCL II KW-0761-002

I

0761-EU-001 KW-07612.7.4.1.1.1

2.5.5.2 0761-0501 0761-002 B

PS LVEF XATL

NHL 90%55)

PaO2 SaO2 SpO2

KW-0761 KW-0761 28

0761-002

KW-0761 2.5

CONFIDENTIAL - 27 -

3 0761-0501DLT 7 0761-002 2

3KW-0761

0761-0501 0.01 0.1 0.5 1.0 mg/kg 1 4 0761-002 1.0 mg/kg 1 8

KW-0761 1.0 mg/kg 18 KW-0761 0761-002

0761-002

0761-0501 ATL MF 1T - PTCL-NOS 2 3 ATL T/NK

2.7.4.1.1.2

2.5.5.3 2.5.5.3-1

2.5.5.3-1

0.01 0.5 4 20100 mg/kg

100 mg/kg2.6.6.2

4 0 0.05 1.2 40 mg/kg/

NOAEL 40 mg/kg/

13 0 2.5 10 40 mg/kg/

NOAEL 40 mg/kg/

0 40 mg/kg/ NOAEL 40 mg/kg/

1.2 mg/kg/4

2.6.6.8.3.1 NOAEL

KW-0761 1 1 4 4 0 0.051.2 40 mg/kg 1 1 13 13

0 2.5 10 40 mg/kg 5/ / / 4 13 40 mg/kg/3

13 40 mg/kg/ 2.6.6.3

20 KW-0761 1 1 18 0 40 mg/kg12 / 140

KW-0761 2.5

CONFIDENTIAL - 28 -

40 mg/kg/2.6.6.6

2.5.5.4 0761-0501 0761-002 KW-0761

ATL PSCCR4

ATL 2.5.5.1

2.7.4.1.3

2.5.5.5

1 0761-0501 KW-0761 0.01 mg/kg 3 0.1 mg/kg 4 0.5 mg/kg

3 1.0 mg/kg 30.01 mg/kg 4 4 4 0.1 mg/kg 4 1 4 0.5 mg/kg 4 4 4 1.0 mg/kg4 4 4 0.1 mg/kg 1

PD0.01 mg/kg 0.04 0.04 0.04 mg/kg

0.1 mg/kg 0.4 0.1 0.4 mg/kg 0.5 mg/kg 2.0 2.0 2.0 mg/kg 1.0 mg/kg 4.0 4.04.0 mg/kg 7 2

KW-0761

2 0761-002 8 8 1 8 mg/kg

27 14 8 13 84 Restaging PD 6

5 11 2

8 7 77 6

42 7

KW-0761 71 2

ATL

1 1/43 KW-0761 2.7.4.1.2

KW-0761 2.5

CONFIDENTIAL - 29 -

2.5.5.6

2.5.5.6.1

1 0761-0501 16 10%2.7.4.2.1.1-1 2.7.4.2.1.1-2 50%

15 93.8% 13 81.3%11 68.8% 10 62.5% 10 62.5%

9 56.3% 8 50.0% CTCAE v3.0 Grade 3

Grade 3 7 Grade 4 3 Grade 3 2 Grade 4 1Grade 3 2 Grade 3 1

Grade 3 1 Grade 3 1Grade 3 1 Grade 3 1- Grade 3 1

Grade 3 1

2 0761-002 27 10%2.7.4.2.1.1-3 2.7.4.2.1.1-4 50%

26 96.3% 24 88.9%23 85.2% 18 66.7% 16 59.3%

14 51.9% 14 51.9% 14 51.9% CTCAE v3.0 Grade 3 Grade 3 9 Grade

4 11 Grade 3 3 Grade 4 2Grade 4 1 Grade 3 8 Grade 3 5

Grade 3 4 Grade 3 3Grade 3 3 - Grade 3 3

Grade 3 2Grade 3 2 Grade 3 1

Grade 3 1 Grade 3 1 Grade 3 1Grade 3 1 Grade 3 1

Grade 3 1 Grade 3 1Grade 3 1 2.7.4.2.1.1

2.5.5.6.2 0761-0501 0761-002 28

0761-0501 6 0761-002 7KW-0761 2.7.4.2.1.2

0761-0501 4 B 10761-002 6 4

KW-0761 2.5

CONFIDENTIAL - 30 -

1 0761-05010761-002 KW-0761

B KW-0761 BB HBc

B HBsHBV-DNA

HBs HBc KW-0761 HBV-DNAHBV-DNA KW-0761

0761-EU-001 B 1KW-0761-001

1 BIV

KW-0761 2 KW-07612.7.4.2.1.3

B

2.5.5.6.3 0761-0501

0 0761-002 9 11 103 2

12 2 2.7.4.2.1.4

2.5.5.7

1 0761-0501 0761-002 KW-0761

KW-0761PaO2 SaO2

0761-002 24 88.9%21 77.8% 16 59.3%

8 29.6% 6 22.2%KW-0761 8 2

2Grade 3 3

Grade 2KW-0761

Grade 2 1

KW-0761 2.5

CONFIDENTIAL - 31 -

2 72

2.7.4.2.1.5

2 KW-0761 ATL

0761-05010761-002 Grade 3 1 3.7%

KW-0761Grade 2

Grade 2 Grade 22.7.4.2.1.5

3 0761-002 18 66.7%

14 51.9% 4 14.8% 2 7.4%1 3.7% 1 3.7% 1 3.7% 1

3.7% 1 3.7% 13.7%

6 1 8 38 8 688 KW-0761 5

118.5 10 288Grade 3

Grade 2

14 KW-0761

2

KW-07610761-002 KW-0761

2.7.4.2.1.5

KW-0761 2.5

CONFIDENTIAL - 32 -

4 0761-002Grade 2 1 Grade 1 1

Grade 1 1Grade 1 Grade 2 Grade 1

Grade 1 2.7.4.2.1.5

2.5.5.8 0761-0501 0761-002 PaO2

SaO2 KW-0761

Grade 3 0761-002 Grade 3 3

LVEF X Grade 20761-002 Grade 2 1

0761-0501 QT 2Grade 2 Grade 1 1 Grade 2 1 0.01 mg/kg KW-0761

Grade 1 28 Grade 2Grade 1 1 1.0 mg/kg KW-0761

7 2KW-0761

0761-002

i KW-0761 CCR4 CCR42.6.6.1.6.3.1

ii 0761-0501 2 QT

iii KW-0761 QT iv SAR 0761-EU-001 QT

0761-002 QT KW-0761 QT

QT/QTc 2.7.4.4

2.5.5.9

1 0761-0501 0761-002

0761-0501 Grade 4G-CSF 1 0761-002 Grade

KW-0761 2.5

CONFIDENTIAL - 33 -

3 G-CSF 1 Grade 4 13

0761-002

13 2 6 2.5

KW-0761 12.5 4014 17.5 KW-0761 27

6900/ L 2 3480/ LGrade 3 8 Grade 3 81 7

2277/ L 576/ L

Grade 3 20 Grade 3 9 Grade 4 1111 6 3

2 9

2938/ L 2 2121/ LGrade 3 5 4 Grade

1 G-CSFATL

ST0761-002

17.0×104/ L 2 11.85×104/ L

Grade 3 5 Grade 3 3 Grade 4 2Grade 4 1 4

Grade 3 3 2 Grade 3 1 Grade 4 2Grade 4 2

Grade 2

2.7.4.3.1

2 0761-002 Grade 3

Grade 4 1 Grade 3 3 -Grade 3 3

Grade 3 2 Grade 3 2Grade 3 1 Grade 3 1

KW-0761 2.5

CONFIDENTIAL - 34 -

Grade 3 1Grade 4 1 - Grade 3 2

Grade 3 1Grade 3 1 Grade 3 1

Grade 3 12.7.4.3.2

2.5.5.10 T KW-0761 CCR4 ATL Th2 T

42,43

KW-07610761-002 T

KW-0761 ATL CD4 CD25CCR4 T CD4 CD25 Foxp3

2 0%Th2 CD4 CCR4

2 CD4 CCR4 0%T CD4 CD25

CD4 CD8 CD4 CD25CD4 CD8 KW-0761

KW-0761 T

2.7.4.3.3

2.5.5.11 KW-0761 0761-0501 0761-002 KW-0761 KW-

07610761-EU-001 2 KW-0761

2.7.4.3.3

2.5.5.12

1 0761-002 65 65

PS 0 1 2

LDH

Staging StagingGrade 2

13 2 8 Grade 280%

2.7.4.5.1

KW-0761 2.5

CONFIDENTIAL - 35 -

2 0761-002 8 KW-0761 3

KW-0761 0761-0023 22

3 KW-0761

3 11

KW-0761

KW-0761 2.7.4.5.2

2.5.5.13 1

1.0 mg/kg13

40 mg/kg/ 2.6.6.3 2

KW-0761

3

40 mg/kg/ 2.6.6.6

KW-0761KW-0761

2.5.5.14 KW-0761 KW-0761

KW-0761

2.7.4.2.1.1.3

1 0761-0501 KW-0761 4 5 PR 1

0.01 mg/kg KW-0761 2

KW-0761 2.5

CONFIDENTIAL - 36 -

KW-0761 Grade 3Grade 3 KW-0761

Grade 3Grade 3 B Grade 2

Grade 1 Grade 2Grade 2 Grade 2

Grade 1 Grade 1 Grade 1 Grade 1 Grade 0 1 Grade 12 B Grade 2 1

2 0761-002 KW-0761 8 13 PR

1 1.0 mg/kg KW-0761Grade 2 Grade 2

Grade 2Grade 2 Grade 1 Grade 1 Grade

0 Grade 0 1KW-0761

2.5.6

2.5.6.1

2.5.6.1.1 CCR4 ATL ATL 1

ATLmLSG15

KW-0761 0761-0501 0761-002

CCR4 ATL 30.8%50.0% 95% 29.9 70.1% 0761-002 95%

29.9% 5% ATL 1 0761-0501

0761-002 100.0% 0761-002 12

0761-0501 0761-002 25.0%0761-0501 0761-002 50.0% 62.5%

KW-0761 2.5

CONFIDENTIAL - 37 -

ATL

0761-002 6565 38.5% 61.5% 65

KW-0761

0761-002 8 11.0mg/kg KW-0761 4

PRPR

KW-0761 CCR4 ATL

2.5.6.2

KW-0761

2.5.6.2.1

2 6G-CSF

ATL ST

KW-0761 ST

2.5.6.2.2

1 KW-0761

0761-00288.9%

Grade 280%

21 77.8% 16 59.3% 8 29.6%

KW-0761 2.5

CONFIDENTIAL - 38 -

6 22.2% KW-0761 82 2

Grade 3 1 Grade 2

Grade 3 3 2KW-0761

Grade 2 1

0761-002 2 72 1

KW-0761

KW-0761

KW-0761

2 0761-002 14 51.9%

4 14.8% 2 7.4% 1 3.7% 13.7% 1 3.7% 1 3.7% 1

3.7% 1 3.7%6 1 8

38 8 68 8 5

118.5 10 288 Grade 3

Grade 2

1 4 KW-0761

KW-0761 43 1 7 14 7 3 14

1 8 KW-0761 KW-0761

KW-0761

ATL KW-0761KW-0761

KW-0761 2.5

CONFIDENTIAL - 39 -

3 B 0761-0501 KW-0761 KW-0761

B 3Grade 3 HBs HBV-

DNA BHBs

HBV-DNA HBc BKW-0761 B

KW-0761 BB ATL KW-0761

HBV-DNA

2.5.6.3 KW-0761 ATL ATL

BCHOP

mLSG15 3 24% 12.722 ATL

13,14)

ATL2007 13

HTLV 2007 ATLATL

18-20) ATL 1

2 5680.8%

KW-0761 CCR4 ADCC

ATL 0761-002 50.0%CCR4 ATL KW-0761

ATL 1100.0% 65

KW-0761KW-0761

ATL

KW-0761 2.5

CONFIDENTIAL - 40 -

KW-0761 CCR4 ATL

KW-0761 2.5

CONFIDENTIAL - 41 -

2.5.7 1. T / .

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3. , , . HTLV-1 . 1 . : ; 2007;16-29. 4. T B . 4 T / ATL

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. . 1996;42(2):231-47. 8. T B . 8 T / ATL

. . 1998;44(3):381-97. 9. T B . 9 T / ATL

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55. ® 10 mg/mL 2010 9