WO 2011/130566
`
`PCT/US2011/032572
`
`1/72
`
`M Fw Fw CD40
`V V
`
`FIG. 1A
`
`a-TUBULIN
`eCD40
`iCD40
`
`y** p***
`
`"ncMw
`
`'jlifrr'
`
`* *
`
`1 2 3 4 5 6 7 8 9 1 0
`FIG. IB
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00491
`
`MYLAN - EXHIBIT 1004 (Part 4 of 13)
`
`
`
`PCT/US2011/032572
`
`1/72
`
`M Fw Fw CD40
`V V
`
`FIG. 1A
`
`a-TUBULIN
`eCD40
`iCD40
`
`y** p***
`
`"ncMw
`
`'jlifrr'
`
`* *
`
`1 2 3 4 5 6 7 8 9 1 0
`FIG. IB
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00491
`
`MYLAN - EXHIBIT 1004 (Part 4 of 13)
`
`
`
`FIG. 2
`SEAP+Fv'-Fvls-RIG-I SEAP+RIG-I-Fv'-Fvls +MyD88-Fv,-Fvls
`iFNb-TA-
`iFNb-TA-
`NFkB-SEAP
`T
`T
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`RAW264. CELLS
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` iRIG, iMyD88 + NFkB REPORTER IN
`
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`NFkB-
`
`m
`
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`
`0.5
`
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`
`2
`
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`
`3
`
`3.5
`
`INDUCTION
`FOLD
`
`0\
`KJ
`
`w
`
`H
`
`C/2 s w
`
`W
`H
`H
`H
`
`CO S C/3
`
`00492
`
`
`
`INDUCTION
`NF-kB
`V
`
`•
`
`FIG. 3
`
`FKBP12V36 DOMAINS
`
`
`
` TURBO (T) CONSTRUCTS: 3
`
`ITLRs
`
`HA EPITOPE
`
`CD40
`OR
`MyD88
`
`T
`
`to o>
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`T
`
`>
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`[
`
`V36
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`DOMAINS .
`DRUG-BINDING
`
`DIMERIZER DRUG
`AP20187/AP1903
`
`SEQUENCE
`MYRISTOYLATION-TARGETING
`
`H
`W
`
`05 s
`m
`H a H
`S
`
`H
`
`00493
`
`
`
`FIG. 4
`
`INDUCTION
`NF-kB
`V
`
`1
`
`a
`
`icTLRs
`
`HA EPITOPE
`
`Ui
`
`>-
`
`t
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`t
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`
`c>
`
`[
`
`V36
`FKBP12
`DOMAINS >
`DRUG-BINDING
`
`DIMERIZER DRUG
`___ AP20187/AP1903
`
`SEQUENCE
`MYRISTOYLATION-TARGETING
`
`to
`w
`
`H
`
`03 s w
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`m
`H
`H
`H
`
`S E/5
`
`00494
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`
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`W0 2011/130566
`
`5/72
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`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00495
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`6/72
`
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`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00496
`
`
`
`WO 2011/130566
`
`7/72
`
`oo o
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`
`SHEET
`
`(RULE
`
`26)
`
`00497
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`8/72
`
`KDa
`175
`120 —
`76 —
`
`50 —
`39 —
`
`28 —
`19 —
`
`RESULTS OF WESTERN
`
`BLOTTING-Ad5-iMyD88
`
`pSX
`
`Un
`
`4a
`
`3b
`
`3a
`
`2b
`
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`
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`
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`
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`b = 100|jl
`
`.v.v.v:"
`
`Un = UNTRANSFECTED CELLS
`pSX = pSHUTTLE-iMyD88
`FIG. 8
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00498
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`9/72
`
`RESULTS OF WESTERN
`BLOTTING
`Ad5-iMyD88L-CD40/Ad5-TLR4On
`2
`3
`4
`5
`Un
`
`1
`
`pSX
`
`175
`120 —
`76 —
`50 —
`39 —
`
`28 —
`
`19 —
`
`6
`
`7
`
`8
`
`9 TLR40n
`
`Un
`
`pSX
`
`175 —
`120 —
`76 —
`50 —
`39 —
`
`''"VXTSMHSV/MF
`
`.3 .
`
`28 —
`
`19 —
`
`Un = UNTRANSFECTED CELLS
`pSX = pSH UTTLE-i MyD88-CD40
`
`FIG. 9
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00499
`
`
`
`FIG. 10
`TREATMENT
`
`>»
`Q
`CO
`CO
`
`O
`Q
`•^1"
`o
`
`O
`Q
`o
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`
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`
`A
`
`O
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`
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`O
`
`A
`
`10
`
`to
`w
`
`100
`
`pg/ml
`
`1000
`
`10000
`
`H
`
`C/5 s w
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`CO s z/i
`
`H
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`
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`
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`
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`
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`
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`
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`
`ELISA
`BMDCs-mlL-12p70
`
`DCs
`
`IN BONE-MARROW DERIVED
`
`IL-12p70 ELISA
`
`RESULTS OF MOUSE
`
`00500
`
`
`
`FIG. 11
`TREATMENT
`
`o
`Q
`•*-
`O
`
`>»
`Q
`OO
`oo
`
`O
`Q
`•'d"
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`
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`
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`
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`CO
`
`•
`
`moOnMAP
`• NOAP
`
`BMDCs- mlL-12p70 ELISA
`
`o-,
`to
`w
`
`H
`w
`
`C/5 s
`ffl
`H
`H a
`H
`CO s z/i
`
`10-
`
`100-
`
`pg/ml
`
`1000 -
`
`10000
`
`00501
`
`
`
`FIG. 12
`
`TREATMENT GROUPS
`
`O
`Q
`•^r
`O o
`+
`Q
`o
`+ 0^0^
`—I
`-si"
`Q. O O
`CO
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`Z 100nMAP DRUG
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`
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`i 1
`4
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`i
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`
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`
`o>
`to
`w
`
`.r"—>
`
`H
`M
`
`C/5 s
`ffl
`H
`a
`H
`CO s
`
`10 H
`
`100 -\
`
`pg/ml
`
`1000 H
`
`10000
`
`00502
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`13/72
`
`Ncol, Nhel
`Pmel
`Apal
`Xbal
`Xhol
`Notl
`Sacll/Kspl
`Ncol
`Pstl
`Xhol
`
`Smal
`BamHI
`BspEI
`Sail
`BsiWI
`Hindlll
`
`Xhol
`Clal
`Smal
`Pvul
`Hindlll
`
`Kan-r
`
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`Mlul
`
`l-Ceul Bglll
`
`t
`
`CMVp
`
`Myr'
`
`pShuttleX-iMyD88E.gcs
`(6303 bp)
`
`MyD88L
`
`Fv'
`
`Fvls
`
`BGHpA
`\
`
`Bglll \>Aflll
`EcoRI \ pst|
`Pmel
`Bglll
`Pl-Scel
`
`FIG. 13
`
`SUBSTITUTE SHEET (RULE 26)
`
`00503
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`14/72
`
`Xhol
`Clal
`
`Pvul
`Hindlll
`
`Bglll
`
`l-Ceul
`
`Muni
`
`Mlul
`
`i
`
`Kan-r
`
`CMVp
`
`SP
`
`pShuttleX-CD4-TLR4L3-E.gcs
`(6037 bp)
`
`mCD4
`
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`Pmel
`Apal
`Xbal
`Xhol
`Notl
`Pstl
`
`Asp718/Kpnl
`
`Xmnl
`
`hTLR4
`L3
`
`Bam HI
`Sphl
`
`BGHpA HA
`I
`n
`
`D-41 n
`Pstl Bglll
`
`'
`pmei
`
`BspEI
`Sail
`
`A f l 1 1 X B S i W I
`
`Hindlll
`
`Pl-Scel
`EcoRI
`Bglll
`
`FIG. 14
`
`SUBSTITUTE SHEET (RULE 26)
`
`00504
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`15/72
`
`Xhol
`Clal
`Smal
`Pvul
`Hindlll
`
`Kan-r
`
`Bglll Mfel/Munl
`
`l-Ceul
`
`i
`
`Mlul
`
`Ncol
`
`CMVp
`
`Myr
`
`MyD88L\ V
`pShuttleX-iMyD88E.CD40.gcs
`(6585 bp)
`
`hCD40
`
`Fv'
`
`Fvls
`
`BGHpA
`\
`
`Bglll
`/EcoRI | Detl
`Pl-Scel
`Bglll
`
`Aflll
`
`Pmel
`
`FIG. 15
`
`Nhel
`Pmel
`Apal
`Xbal
`Xhol
`Notl
`Sacll/Kspl
`Ncol
`Pstl
`Xhol
`
`Smal
`
`BamHI
`BspEI
`Sail
`BsiWI
`Hindlll
`
`SUBSTITUTE SHEET (RULE 26)
`
`00505
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`16/72
`
`NO DRUG
`
`1250 -i • 100nM DRUG
`
`1000-
`
`pg/ml
`
`750 -
`
`500-
`
`250-
`
`S3
`
`Q ii pa i—
`i
`6.25
`12.5
`
`i
`
`25
`
`50
`
`100
`
`MOI OF Ad5.iMyD88.CD40
`
`FIG. 16
`
`SUBSTITUTE SHEET (RULE 26)
`
`00506
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`17/72
`
`CD
`ZD
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`ZD
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`
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`CO
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`
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`
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`
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`
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`
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`
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`
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`
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`Q_
`CM
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`"O Q_
`< <
`
`SUBSTITUTE SHEET (RULE 26)
`
`00507
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`18/72
`
`1500-|
`
`1000-
`
`IL-12p70, pg/ml
`
`500-
`
`0
`
`O
`O
`CO
`Q_
`+
`o
`3
`
`Q
`O
`CO
`CL
`+
`o
`Q
`O
`
`T
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`Q
`
`CO
`Q_
`+
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`Q
`O
`
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`
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`•
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`oo
`CO
`O
`
`Q
`O
`+
`o
`Q
`o
`CO
`CO
`Q
`
`FIG. 18
`
`SUBSTITUTE SHEET (RULE 26)
`
`00508
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`19/72
`
`PBS
`DCs+CD40L+LPS
`DCs+Ad-Luc+AP
`DCs+Ad-iCD40+LPS+AP
`DCs+Ad-iMyD88
`DCs+Ad-iMyD88+AP
`DCs+Ad-iCD40-iMyD88
`DCs+Ad-iCD40-iMyD88+AP
`
`2.5 -i
`
`2 . 0 -
`
`1.5-
`
`1.0-
`
`0.5-
`
`TUMOR „
`VOLUME (cm )
`
`0.0
`
`0
`
`T
`5
`
`T
`10
`
`T
`15
`DAYS
`
`FIG.19A
`
`-V-
`
`•V-
`
`T
`20
`
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`
`•V
`T
`25
`
`PBS
`H
`
`Luc + LPS
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`P
`
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`+ LPS
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`
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`
`11
`
`FIG. 19B
`
`SUBSTITUTE SHEET (RULE 26)
`
`00509
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`20/72
`
`«-PBS
`DCS+CD40L+LPS
`•— DCs+Ad-Luc+AP
`DCs+Ad-iCD40+LPS+AP
`DCs+Ad-iMyD88
`DCs+Ad-iMyD88+AP
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`^ DCs+Ad-iCD40-iMyD88+AP
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`VOLUME (cm )
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`5
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`0
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`T
`10
`
`-v-
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`15
`
`T
`20
`
`->7-
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`T
`25
`
`DAYS
`
`FIG. 19C
`
`SUBSTITUTE SHEET (RULE 26)
`
`00510
`
`
`
`( 9 Z H'iiiH) xaaHS ainiusans
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`IE ro
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`00511
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`22/72
`
`\
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`CQ
`=5
`Z
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00512
`
`
`
`FIG. 22
`
`ANALYSIS OF RECIPIENT SPLEENS
`AFTER 6-16 h PERFORM FACS
`
`>•
`
`(4x106 CELLS)
`I.V. ADMINISTRATION
`
`CFSEhl/SIINFEKL
`
`LABELED AT 2 CFSE DOSES
`
`CFSElo/TRP2
`
`NAIVE SPLENOCYTES
`
`CFSE
`
`76% LYSIS
`
`M
`
`k
`
`50%
`
`50%
`
`to
`w
`
`H
`W
`
`C/5 s
`H m
`H
`H
`z/i
`S
`
`CO
`
`00513
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`24/72
`
`90-1
`8 0 -
`70-
`6 0 -
`50-
`% SPECIFIC LYSIS
`40-
`30-
`2 0 -
`1 0 -
`0
`
`*
`
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`Q_
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`Q
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`CD
`CO
`Q
`Q
`O
`oo
`OO
`Q
`
`FIG. 23
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00514
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`25/72
`
`PBS
`SPLEENS-S1
`
`19±12%
`
`3(H ii
`
`COUNT
`
`25 A
`20A
`15-=
`10^
`
`0 J I
`
`I
`
`I
`
`II I Ij
`2
`10
`
`4
`3
`10
`10
`CDS FITC-A
`
`5
`10
`
`CD40L+LPS
`
`SPLEENS-S22 n
`
`20±14%
`
`150^
`mz_
`COUNT
`50 ~
`
`O ^TTTTTT
`2
`10
`
`Itiy,
`4
`3
`10
`10
`CD8 FITC-A
`
`?
`
`
`I I I I l |
`5
`10
`
`Luc+LPS+CID
`SPLEENS-S9
`
`125^ n
`
`100^
`75^
`COUNT 50^
`25^
`0
`
`2
`10
`
`3
`4
`10
`10
`CD8 FITC-A
`
`FIG. 24
`
`12±1%
`
`n riiii|
`5
`10
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00515
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`26/72
`
`iCD40+LPS+CID
`SPLEENS-S19
`
`47±6%
`
`35"=
`30-1
`25-1
`20-=
`COUNT 15-1
`10-1
`
`0^ I I I I I llj
`2
`10
`
`15 -E
`
`10
`
`5 _
`
`COUNT
`
`0 I I I I I l
`2
`10
`
`j
`
`l
`
`Ji
`^ i V i t o n
`4
`3
`10
`105
`10
`CDS FITC-A
`
`iMyD88+CID
`SPLEENS-S18
`
`45±3%
`
`•M
`4
`3
`10
`10
`CDS FITC-A
`
`105
`
`FIG. 24 Continued
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00516
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`27/72
`
`90-3
`80—
`70-E
`60-=
`50-E
`40-i
`COUNT 30^
`20^
`1 0 - =
`0
`
`rTT
`
`iMyD88CD40
`
`SPLEENS-S12
`
`55±4%
`
`1 TT
`
`2
`10
`
`3
`10
`CDS FITC-A
`
`4
`10
`
`T
`
`5
`10
`
`90-
`80-
`70-
`60-
`50-
`40-
`COUNT 30
`i
`20
`10
`0
`
`TTT
`
`iMyD88CD40+CID
`
`SPLEENS-S23
`
`J
`
`68±15%
`
`r~r
`
`2
`10
`
`4
`
`4
`3
`10
`10
`CD8 FITC-A
`
`iTnT]—r
`5
`10
`
`FIG. 24 Continued
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00517
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`o
`o
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`CO
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`CO
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`
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`CO
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`3
`
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`
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`
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`
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`
`28/72
`
`Tp
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
`•<
`
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`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00518
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`29/72
`
`o
`o
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`
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`
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`
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`
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`
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`
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`
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`
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`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00519
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`30/72
`
`3.0 n
`
`2.5
`
`2 . 0 -
`
`TUMOR
`VOLUME (cm ) 1.5-
`
`1 . 0 -
`
`0.5-
`
`PBS
`CD40L+LPS
`^
`Luc+LPS+AP1903
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`iMyD88.CD40+AP1903
`
`8
`
`10
`
`20
`25
`15
`DAYS AFTER TUMOR INOCULATION
`
`30
`
`FIG. 26A
`
`3.0-|
`
`2.5-
`
`2 . 0 -
`
`*- PBS
`e— 1,250 VP/c
`1,250 VP/c iMyD88.CD40+AP1903
`
`iMyD88.CD40
`
`TUMOR .
`VOLUME (cm )
`
`1-5
`
`^ 20,000 VP/c iMyD88.CD40
`
`»- 20,000 VP/c iMyD88.CD40+AP1903
`
`1 . 0 -
`
`0.5-
`
`8
`
`10
`
`20
`25
`15
`DAYS AFTER TUMOR INOCULATION
`
`30
`
`FIG. 26B
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00520
`
`
`
`O
`O O
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`Q w
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`
`FIG. 26C
`
`>.
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`V77\ X77A
`
`-500-1
`
`0
`
`500-
`
`1000-
`
`1500
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`IL-12p70, pg/mL
`
`2000-
`
`2600-
`
`3000-
`
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`
`H
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`H w
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`H
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`
`00521
`
`
`
`(9Z H'iiiH) xaaHS
`
`ainiusans
`
`SIINFEKL-H2-Kb-PE
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`
`u
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`
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`PBS
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`<
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`
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`
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`
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`
`00522
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`
`WO 2011/130566
`
`PCT/US2011/032572
`
`33/72
`
`PBS
`06172009-2801
`
`70-
`60-
`50-
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`COUNT 30-
`20-
`10-
`0 -
`
`TT
`
`2
`10
`
`3
`4
`10
`10
`CFSE FITC-A
`i MyD88.CD40+AP1903
`06172009-2838
`
`1.98%
`
`I
`HI
`5
`10
`
`94.8%
`
`COUNT
`
`50^
`40-E
`30€
`20r
`10^
`0
`
`I
`102
`
`fj ^
`103
`104
`CFSE FITC-A
`
`105
`
`80 -
`70 -
`60 -
`50 -
`40 _
`3 0 -
`20 -
`
`%
`SPECIFIC
`LYSIS
`
`V,
`
`VA
`
`V,
`
`V/.
`
`10 - ww^wwww
`
`^Ppg^
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`PBS LLPS++
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`FIG. 273
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00523
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`34/72
`
`250-1
`
`CO
`LU O
`(O o
`CO
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`Q_
`CO
`LL o
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`=3
`
`50-
`
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`
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`
`50-
`
`40-
`
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`
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`
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`'A
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`KTI& +AP1903 +AP1903 +LPS
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`I
`
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`+AP1903
`
`FIG. 27C
`
`^ ^ O T - 2
`
`TRP-2
`
`PBS
`
`Luc+LPS
`+AP1903
`
`Z?
`'A
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`A
`A
`A
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`A A
`A
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`Vs.
`A
`A
`^rS
`iMyD88. iMyD88. CD40L
`CD40 CD40
`+LPS
`+AP1903
`
`2
`iMyD88
`iCD40+
`+AP1903 LPS
`+AP1903
`FIG. 27D
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00524
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`35/72
`
`%
`SPECIFIC
`LYSIS
`
`%
`SPECIFIC
`LYSIS
`
`90 -i
`8 0 -
`70-
`6 0 -
`50-
`40-
`3 0 -
`2 0 -
`1 0 -
`0
`
`90 -i
`8 0 -
`70-
`6 0 -
`50-
`4 0 -
`30-
`2 0 -
`1 0 -
`0
`
`YAC-1
`
`25:1
`
`50:1
`
`75:1
`E:T
`
`100:1
`
`EL-4
`
`T
`25:1
`
`T
`
`50:1
`
`T
`
`75:1
`E:T
`
`T
`
`100:1
`
`FIG. 28
`
`PBS
`CD40L+LPS
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`iCD40+LPS+CID
`-o-
`iCD40+LPS
`iMyD88.CD40+CID
`iMyD88.CD40
`iMyD88+CID
`
`PBS
`CD40L+LPS
`LUC+LPS+CID
`-o- iCD40+LPS+CID
`iCD40+LPS
`iMyD88.CD40+CID
`iMyD88.CD40
`iMyD88+CID
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00525
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`36/72
`
`EG7 - EXPERIMENT 2 IMMUNE
`
`MONITORING DATA SUMMARY
`CTL ASSAY
`
`EG-7
`
`%
`SPECIFIC
`LYSIS
`
`%
`SPECIFIC
`LYSIS
`
`90 -i
`8 0 -
`70-
`6 0 -
`50-
`40-
`30-
`2 0 -
`1 0 -
`0
`
`90 -i
`8 0 -
`70-
`6 0 -
`50-
`4 0 -
`3 0 -
`2 0 -
`1 0 -
`0
`
`75:1
`
`¥
`100:1
`
`25:1
`
`50:1
`
`E:T
`
`EL-4
`
`T
`25:1
`
`T
`50:1
`
`75:1
`
`T
`
`100:1
`
`E:T
`
`FIG. 29
`
`PBS
`CD40L+LPS
`LUC+LPS+CID
`iCD40+LPS+CID
`iCD40+LPS
`iMyD88.CD40+CID
`iMyD88.CD40
`iMyD88+CID
`
`PBS
`CD40L+LPS
`LUC+LPS+CID
`^ iCD40+LPS+CID
`iCD40+LPS
`iMyD88.CD40+CID
`iMyD88.CD40
`iMyD88+CID
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00526
`
`
`
`+CID
`iMyD88
`
`D88+CI
`iCD40.M
`
`FIG. 30
`+CID
`+CID
`iCD40.MyD88
`iCD40+LPS
`Luc+LPS
`
`MC
`
`CD40L+LPS
`
`wt
`
`P7;
`
`DONOR#3
`
`0
`
`50-
`
`100-
`
`tfc
`CO
`o Q_
`CO 150-
`o
`o
`o
`o
`o 200-
`O
`LU
`
`CO
`
`250-
`
`300-
`
`350-1
`
`o>
`to
`w
`
`.r"—>
`
`H
`W
`S
`H m
`H
`H
`
`05
`
`co S z/i
`
`00527
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`38/72
`
`I—
`CO
`
`CM
`CD
`
`D_ <
`O
`3
`-O <
`
`CD Q.
`O
`CO
`
`to O o
`CQ
`E
`o
`o
`3 =>
`
`O
`LU
`Df
`Q_ =)
`CC o
`O
`
`CZ3
`
`CO o
`
`CM
`CD
`
`CD
`
`CD
`C3
`
`CD
`
`CO
`CD
`
`CM
`CD
`
`CD
`
`CD
`CD
`
`ej
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00528
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`39/72
`
`r—
`CO co
`
`CD
`-^d-CM
`
`Q_ <
`O
`•o <
`
`CO
`Q_
`
`CO o a
`ca
`E
`O
`o
`3 ZD
`
`O
`LU
`D_ =)
`c£
`O
`O
`
`CZ3
`
`CO o
`
`CM
`CD
`
`CD
`
`T
`
`CD o
`
`o
`
`•*s-
`CD
`
`co
`CD
`
`CM
`CD
`
`CD
`
`CD
`CD
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00529
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`40/72
`
`r«-
`CO
`
`co
`CO
`D_
`CN Q_ _
`<C +
`o ^ o>
`+
`o cvi O
`CD
`Q_
`Z3
`CO
`-Q n
`O
`to <3;
`
`-Q
`<
`
`CSI CO
`
`•^r i
`
`CM
`
`CD
`OO
`
`O
`CO
`
`CD
`•^1-
`
`O
`CM
`
`CD
`
`XVIAI dO %
`
`c/> o Q
`
`CD
`E
`O
`o
`5 ZD
`CD
`LU Od
`Q_ =>
`cd o o
`
`CO
`
`T
`CD
`CD
`
`SUBSTITUTE SHEET (RULE
`
`26)
`
`00530
`
`
`
`wo
`
`2011/130566
`
`pct/us2011/032572
`
`41/72
`
`Pad
`
`Pad
`
`l-Ceul Notl
`
`Pl-Scel
`
`Amp-R
`
`RITR
`
`LITR
`CMVp~iCD40 ^
`bGHpA
`
`Notl
`
`2E3
`
`Ad5f35-ihCD40f
`(34572 bp)
`
`Notl
`
`Notl
`
`Notl
`
`Notl
`
`Notl
`
`FIG. 33
`
`
`
`
`
`SUBSTITUTE SHEET (RULE 26)
`
`00531
`
`
`
`FIG. 34
`
`PSA PROGRESSION AS > 25% INCREASE
`
`EXPECTED OVERALL SURVIVAL IN CRPC (CLIN. CAN.
`INCREASED EXPECTED OVERALL SURVIVAL
`
`RES, 2005)
`IL-6 VALUE BELOW 13.3 PG/ML SHOWN TO CORRELATE WITH INCREASED
`5.
`4. CTC VALUE BELOW 5 CELLS PER 7.5 ML SHOWN TO CORRELATE WITH
`FROM NADIR
`3. PCWG2 FAVORS USE OF WATERFALL PLOT TO ASSESS PSA RESPONSE, AND DEFINES
`MEASURABLE
`2. PER PCWG2. STABLE DISEASE (< 1 NEW LESION) OR PROGRESSIVE DISEASE (> 2 NEW LESIONS). RESPONSE NOT RELIABLY
`ENHANCEMENT (DISCUSSED IN LATER SLIDE)
` INCREASE IN TUMOR BURDEN). VASCULARITY PER NON-VALIDATED CR, PR, SD, PD CLASSIFICATIONS, BASED ON CT CONTRAST
`
`
` TUMOR BURDEN); PARTIAL RESPONSE (>30% DECLINE IN TUMOR BURDEN); STABLE DISEASE; PROGRESSIVE DISEASE (>20%
`1. LESION SIZE PER RECIST 1.1 & PROSTATE CANCER WORKING GROUP 2
`(PCWG2): COMPLETE RESPONSE (ELIMINATION OF
`
`CORRELATION WITH CLINICAL OUTCOME
`
`FAVORABLE OR UNFAVORABLE5
`
`FAVORABLE OR UNFAVORABLE4
`
`INCREASE <25% OR >25%; DECREASE
`WATERFALL PLOT3
`SD ORPD2
`CR, PR, SD ORPD
`1
`
`CHANGE VS. BASELINE
`CTL, CYTOKINES, ELISPOT
`CHANGE VS. BASELINE
`CELLS PER 7.5 mL
`PSADT
`CHANGE VS. BASELINE
`NEW BONE LESIONS
`LESION SIZE; VASCULARITY
`
`CLASSIFICATION
`
`ASSESSMENT
`
`KPS, PAIN SCORE
`IMMUNE RESPONSE PROFILE
`
`SYMPTOMS
`IMMUNOLOGIC
`
`IL-6
`CIRCULATING TUMOR CELLS
`
`PSA
`
`BIOCHEMICAL
`
`BONE (BONE SCAN, MRI)
`SOFT TISSUE (CT.MRI)
`
`RADIOGRAPHIC
`
`MODALITY
`
`EXPLORATORY EFFICACY ASSESSMENTS
`
`to
`w
`9
`h
`w
`C/5 s
`
`ffl
`h
`
`h
`h
`z/i
`S
`
`CO
`
`00532
`
`
`
`FIG. 35
`
`OO
`
`OO
`
`298%
`
`PSADT INCREASE
`
`80%
`2.9
`PD
`PD
`
`N/A
`N/A
`PD
`
`N/A
`1
`WEEKS
`
`-75%
`43%
`IL-6, MCP-1
`
`+139%
`72%
`IL-6, MCP-1
`
`1.6
`30.9
`5
`NONE
`8
`90%
`73
`
`1006
`
`1.4
`69.0
`4
`NONE
`8
`100%
`66
`
`1005
`
`118%
`3.7
`SD
`
`1004
`
`PSA\
`PSA\
`SD
`SD
`SD
`SD
`2
`1
`2
`1
`SAFETY & CLINICAL RESPONSE @
`12
`-98%
`-65%
`-100%
`-16%
`-6%
`-2%
`283%
`66%
`AG-SPECIFIC IMMUNE RESPONSE IFN-y, IP-10
`NOT DETERMINED
`IFN-y, IP-10
`
`
`12 IMMUNOLOGICAL RESPONSE @ WEEKS
`4.9
`7.3
`5.0
`1.7
`11.1
`5.8
`312.8
`46.5
`4
`5
`3
`4
`NONE
`NONE
`TAXOTERE TAXOTERE
`10
`7
`9
`N/A
`80%
`80%
`90%
`90%
`81
`80
`72
`73
`DEMOGRAPHICS & BASELINE METRICS
`1002
`1001
`1003
`12 WEEK IMMUNOLOGICAL & CLINICAL RESPONSE SUMMARY
`
`(MOS.) 19.5
`SD
`
`POST-TREATMENT PSADT
`RECIST 1.1-BONE
`RECIST1.1-SOFT TISSUE
`MAX AE GRADE
`
`IL-6 DECLINE @ WEEK 12
`MEAN POST-DOSE CYTOKINE A
`
`(MOS.)
`
`PRE-TREATMENT PSADT
`(ng/mL)
`BASELINE PSA
`CLINICAL SUBTYPE
`PRIOR CHEMOTHERAPY
`GLEASON SCORE
`
`KPS (AT SCREENING)
`AGE
`
`SUBJECT#
`
`<7\
`to
`w
`9.
`
`h
`ffl
`
`00 S
`I—I a
`
`ffl
`h
`
`h
`w
`S
`
`CO
`
`00533
`
`
`
`FIG. 36
`
`>50%
`
`>30%
`
`O
`
`a
`
`PSA
`
`INFORMAL PR
`
`FORMAL PR
`
`D
`
`VASCULARITY
`
`MEASURABLE METASTATIC DISEASE
`
`WATERFALL PLOTS -12 WEEK CHANGE FROM BASELINE
`
`-100%
`
`-75%
`
`-50%
`
`-25%
`
`0%
`
`25%
`
`-100%
`
`-75%
`
`-50%
`
`-25%
`
`0%
`25%
`
`QG
`
`O o
`x
`LU
`
`o
`<
`
`a s
`o
`o
`CD
`O
`<
`
`to
`w
`
`h
`w
`C/5 S
`m
`h
`
`h
`h
`z/i
`S
`
`CO
`
`00534
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`45/72
`
`9-11
`dSO-NO
`DlrdlW
`\ $i-dm
`i-don
`A-Ndl
`S31NVy
`\ D-dNl
`\ {H-dl
`
`'0
`) »
`MP
`b®
`iZIE^pO
`
`IN.
`
`o
`
`CD
`
`oo
`
`\
`
`\
`
`a—"—
`
`to
`
`I Or
`1 0
`0 0 0
`F^PV, 8
`) 0
`fl
`
`un
`
`44:
`LU co
`
`CNJ
`
`o
`CO
`CO
`cslf
`oo
`
`LO
`LO
`
`CNJ
`
`•^d"
`CNI
`oo
`
`Si
`
`oo
`Ovi
`
`92 \l ooj
`
`O
`CD
`
`CD
`CO
`
`CD
`co
`
`CD
`•^d"
`
`CD
`CM
`
`CD
`
`M33AA I @ S3SV3yONI QlOd
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`OO
`o
`CD
`
`o
`LU
`CQ
`=3
`C/3
`to
`LU
`
`Q_
`CO
`LU
`
`5^
`O
`o
`
`00535
`
`
`
`NOT RELIABLE
`(3.2-10,OOOpg/mL) ARE
`STANDARD RANGE
`VALUES OUTSIDE
`CYTOKINE ANALYSIS.
`MULTIPLEX SERUM
`RESULTS FROM
`
`+ INJECTIONS
`
`-*-1005*
`
`-x-1004
`
`FIG. 38
`
`30
`
`28
`
`26
`
`24
`
`22
`
`20
`
`18
`
`16
`
`WEEKS
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`x; / s.
`
`A
`
`0
`
`200
`
`11
`
`300
`
`c 400
`CD
`E
`
`500
`
`600
`
`A
`
`700 A
`
`800
`
`900
`
`to
`
`.r"—>
`
`H
`M
`
`9 w
`C/5 s
`w
`H
`H
`H
`z/i
`S
`
`CO
`
`K
`o o
`
`o o
`o o o
`o o o o o
`m
`CM
`CO
`CD
`
`-100%
`-75%
`-50%
`-25% -LI
`0%
`25%
`
`12 WEEK CHANGE
`
`VCAM-1 BIOMARKER
`
`00536
`
`
`
`(1 DOSE)^
`
`o o
`
`CO
`
`O
`CM
`i=r
`
`O
`<35
`
`FIG. 39
`
`o
`o
`
`o
`CM
`
`O
`
`o
`
`>50%
`
`>30%
`
`o
`o
`CO
`
`o
`o
`CO
`
`(WEEK 9)
`(5 DOSES)
`
`4 DOSES) °
`O
`h^
`
`12 WEEK PSA WATERFALL PLOT
`
`-100%
`
`-75%
`
`•50%
`
`-25%
`
`0%
`25%
`
`50%
`
`75%
`
`100%
`125%
`
`150%
`
`175%
`
`200%
`
`o>
`to
`w
`£
`
`H
`W
`
`C/5 S
`
`ffl
`H
`H
`H
`w
`
`CO s
`
`00537
`
`
`
`13x10 mm
`W/A ^
`
`f
`
`fJmi
`
`25x21 mm
`
`: :•
`
`m
`
`m
`
`ill
`Wi
`
`FIG. 40
`
`19x16 mm
`
`w A
`
`31x24 mm
`
`J
`
`Wy
`
`P*
`
`wi
`
`25x23 mm
`
`m
`f'Tt
`
`s
`
`4 ^
`•
`
`36x29 mm
`»—
`
`ffi
`
`^ 1
`'it. • '
`W
`,s/"$A
`
`•/J?
`
`LU
`
`5
`
`D_
`LU
`CN
`1
`§ O U-
`
`
`CO
`
`o>
`to
`W
`
`.r"—>
`
`H
`M
`
`C/5 s
`
`ffl
`H
`H
`H
`S
`
`CO
`
`LU
`
`s
`
`D_
`LU
`
`O
`Ll_
`CO
`
`WEEK-52
`
`WEEK-12
`
`W3
`
`WAfi
`
`BASELINE (WEEK-7)
`
`SUBJECT 1003: TUMOR SHRINKAGE & ANTIVASCULAR EFFECT
`
`00538
`
`
`
`wo
`
`2011/130566
`
`pct/us2011/032572
`
`49/72
`
`SUBJECT 1003: SOFT TISSUE PARTIAL RESPONSE
`
`LD
`
`SD
`
`NORMAL LN SIZE RANGE
`
`e
`e
`LU
`INI
`CO
`LU
`CD
`
`LU
`>
`<
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`-8
`
`0
`
`48
`40
`32
`24
`16
`8
`WEEKS RELATIVE TO FIRST DOSE
`
`56
`
`FIG. 41
`
`
`
`
`
`SUBSTITUTE SHEET (RULE 26)
`
`00539
`
`
`
`FIG. 42
`
`WEEKS
`
`36
`
`32
`
`28
`
`24
`
`20
`
`16
`
`12
`
`8
`
`4
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`i
`
`-x-uPAR
`
`•-
`
`•n
`
`P
`
`SUBJECT 1003
`
`0
`
`1
`
`10
`
`Q_
`en
`E
`
`100
`
`\ t
`
`1,000
`
`10,000
`
`o>
`to
`w
`
`H
`W
`
`in s
`
`m
`H
`H
`H
`
`CO S z/i
`
`00540
`
`
`
`FIG. 43
`WEEKS RELATIVE TO FIRST DOSE
`-24
`-16
`-8
`48
`40
`24
`32
`8
`16
`0
`MMtt-4-4-4-4-4
`TR0FEX//TR0FEX
`
`64
`
`56
`
`4
`/
`
`r
`
`/
`
`77^
`
`/Z
`/
`CT
`
`7
`/
`/
`/
`
`/
`/
`/
`/
`/
`/
`/
`/
`/
`
`TAXOTERE
`/
`
`-32
`
`-40
`
`-48
`
`-56
`
`-64
`
`-72
`
`-80
`
`•/1/h i~bf
`/
`/
`/
`/
`
`/
`/
`/
`/
`/
`/
`
`/
`/
`
`/
`/
`/
`/
`/
`/
`
`/
`/
`7
`/
`/
`/
`/
`/
`/
`
`/
`/
`7
`/
`/
`/
`
`/
`
`/
`7
`/
`/
`Z
`/
`/
`/
`/
`/
`7
`/
`/
`/
`
`0
`
`500
`
`1,000
`
`1,500
`
`2,000
`
`2,500
`
`3,000
`
`Q_
`CO
`<
`oi
`E
`
`d
`
`o>
`to
`w
`9
`
`H
`W
`
`C/5 S
`
`ffl
`H
`H
`H
`
`CO S
`
`MONTHS
`
`KPS 90 AT 21
`
`
`
` PSA: SUBJECT 1003 - ALIVE WITH
`
`00541
`
`
`
`FIG. 44
`DOMAIN OF CD40 (188 aa)
`CD40 c = CYTOPLASMIC
`LINKER (6 aa)
`Is = SHORT G-S
`
` Fv = "WOBBLED CODONS" FKBP12
`Fv = FKBP12 (V36) (107 aa)
`
` Myr = MYRISTOYLATION-TARGETING SEQUENCE
`KEY (NOTE: ALL
`
`
`
` HUMAN-DERIVED SEQUENCE EXPECT LINKER):
`Fv
`Fv
`
`(V36) (107 aa)
`
`FROM c-Src (14 aa)
`
`CD40c
`
`Is
`
`to
`w
`
`Myr
`
`iCD40 (~35kDa)
`
`(31605 bp)
`Ad5f35-ihCD40
`
`iCD40
`
`LITR
`
`CMVp
`
`H
`
`C/5 s M
`
`H m
`H
`H
`
`s ZA
`
`00542
`
`
`
`30
`
`HIGH SHOWN AS 10,000 pg/mL
`NOT RELIABLE. VALUES OOR
`RANGE (3.2- 10,000
`
` VALUES OUTSIDE STANDARD
`
` SERUM CYTOKINE ANALYSIS.
`RESULTS FROM MULTIPLEX
`
`-o- HGF
`EGF
`Hj- INJECTIONS
`RANTES
`-*- IFN-Y
`MCP-1
`MIP-1P
`MIP-1a
`GM-CSF
`
`FIG. 45
`WEEKS
`10
`12
`14
`6
`8
`2
`4
`0
`16 18
`0.1 |»|»|»|»|»|» •
`
`20
`
`22 24 26 28
`
`>/ h
`
`5
`
`3r-f
`
`A.
`
`•A—11-A—.i—
`
`«•
`
` - SUBJECT 1001
`
`
`SERUM MARKERS
`
`pg/mL
`
`10
`
`100
`
`1000
`
`10000
`
`.r^->.
`
`to o>
`w
`9
`H
`w
`C/5 s
`
`m
`H
`H
`H
`
`CO S z/i
`
`00543
`
`
`
`OOR LOW SHOWN AS 0.1
`HIGH SHOWN AS 10,000 pg/mL;
`NOT RELIABLE. VALUES OOR
`
` RANGE (3.2- 10,000 pg/mL) ARE
` VALUES OUTSIDE STANDARD
`
`SERUM CYTOKINE ANALYSIS.
`RESULTS FROM MULTIPLEX
`HGF
`EGF
`-j- INJECTIONS
`RANTES
`IFN-Y
`MCP-1
`MIP-1P
`MIP-1a
`GM-CSF
`
`FIG. 46
`WEEKS
`12 14 16 18
`•
`
`20 22 24 26 28
`i
`
`30
`
`10
`
`8
`
`6
`
`2
`4
`0
`0-1 f * I * If
`
`IP*
`
`J2
`
`-IF-*
`
`•<-=3r
`
`X
`
`§
`
` - SUBJECT 1002
`SERUM MARKERS
`
`pg/mL
`
`10
`
`100
`
`1000
`
`10000
`
`.r^->.
`
`H
`
`to o>
`£ W
`C/5 s w
`m
`H
`H a
`H
`CO S z/i
`
`00544
`
`
`
`30
`
`OOR LOW SHOWN
`HIGH SHOWN AS 10,000 pg/mL
`NOT RELIABLE. VALUES OOR
`RANGE (3.2- 10,000
`
` VALUES OUTSIDE STANDARD
` SERUM CYTOKINE ANALYSIS.
`
`RESULTS FROM MULTIPLEX
`-o- HGF
`EGF
`-jj- INJECTIONS
`RANTES
`IFN-Y
`MCP-1
`MIP-1P
`MIP-1a
`GM-CSF
`
`FIG. 47
`WEEKS
`14
`16 18
`
`20
`
`22 24 26 28
`
`1
`
`10
`12
`* '
`
`8
`
`'
`
`6
`
`4
`
`2
`
`1
`
`0
`0.1 J
`
`' M
`
`pg/mL
`
`10
`
`100
`
`J L
`
`1000
`
`10000
`
`-^zr
`
`/ s
`
`i
`
`5:
`
`fit
`
`2
`
` - SUBJECT 1003
`
`
`SERUM MARKERS
`
`to
`w
`
`.r"—>
`
`H
`W
`
`C/5 s
`
`W
`H
`H
`H
`
`CO S z/i
`
`00545
`
`
`
`HIGH SHOWN AS 10,000 pg/mL
`NOT RELIABLE. VALUES OOR
`RANGE (3.2- 10,000
`
` VALUES OUTSIDE STANDARD
` SERUM CYTOKINE ANALYSIS.
`
`RESULTS FROM MULTIPLEX
`
`HGF
`EGF
`Hj- INJECTIONS
`RANTES
`IFN-Y
`MCP-1
`MIP-1P
`MIP-1a
`GM-CSF
`
`FIG. 48
`WEEKS
`10
`12
`4
`
`14
`
`20
`
`18
`
`16
`
`8
`4
`
`4
`6
`4—4
`
`2
`4
`
`0
`11
`
`*
`
`*
`
`10 «
`
`§;
`
`' F
`
`100
`
`pg/mL
`
`•
`
` - SUBJECT 1004
`
`
`SERUM MARKERS
`
`1000
`
`10000
`
`to
`w
`
`H
`W
`
`C/5 s
`H m
`H a
`H
`CO S z/i
`
`00546
`
`
`
`HIGH SHOWN AS 10,000 pg/mL
`NOT RELIABLE. VALUES OOR
`RANGE (3.2- 10,000 pg/mL) ARE
` VALUES OUTSIDE STANDARD
`
`SERUM CYTOKINE ANALYSIS.
`RESULTS FROM MULTIPLEX
`
`HGF
`EGF
`INJECTIONS
`-J-
`RANTES
`IFN-Y
`MCP-1
`MIP-ip
`MIP-1a
`GM-CSF
`
`FIG. 49
`WEEKS
`10
`12
`
`14
`
`20
`
`18
`
`16
`
`8
`
`6
`
`4
`2
`0
`o.i i—$—4—t
`
`• !fe
`
`sg
`
`- SUBJECT 1005
`SERUM MARKERS
`
`to
`w
`
`H
`w
`C/5 i
`H m
`H
`H
`
`CO S z/i
`
`10
`
`100
`
`pg/mL
`
`<•
`
`1000
`
`10000
`
`00547
`
`
`
`HIGH SHOWN AS 10,000 pg/mL
`NOT RELIABLE. VALUES OOR
`RANGE (3.2- 10,000 pg/mL) ARE
` VALUES OUTSIDE STANDARD
`
`SERUM CYTOKINE ANALYSIS.
`RESULTS FROM MULTIPLEX
`
`-o- HGF
`EGF
`-jj- INJECTIONS
`RANTES
`IFN-Y
`-*- MCP-1
`MIP-ip
`MIP-1a
`GM-CSF
`
`-K-
`
`FIG. 50
`WEEKS
`10
`12
`f
`
`14
`
`20
`
`18
`
`16
`
`8
`
`6
`
`4
`
`2
`
`0
`0.1 ^
`
`.i—»
`
`-*—"—»
`
`52!
`
`3
`
`*
`
`-7$.
`
` - SUBJECT 1006
`
`
`SERUM MARKERS
`
`pg/mL
`
`10
`
`100
`
`)'?
`
`1000
`
`10000
`
`to o>
`w
`
`.r^->.
`
`H
`w
`
`C/5 s
`
`m
`H
`H
`H
`
`CO S z/i
`
`00548
`
`
`
`Ad5f35
`
`2
`
`tS=3
`
`z
`z
`z
`
`7
`
`FIG. 51
`OVALBUMIN
`
`PSMA
`
`Ox
`
`1x
`
`z X
`z
`X
`
`2x
`
`NO ANTIGEN
`CHANGE VS.
`
`3x
`
`4x
`
`SITE IMMUNE RESPONSE (1006)
`
`INJECTION
`PSMA-SPECIFIC
`
`o>
`to
`w
`
`.r"—>
`
`H
`W
`
`C/5 s
`H m
`H
`H
`
`CO S z/i
`
`00549
`
`
`
`WEEKS RELATIVE TO FIRST DOSE
`
`WEEKS RELATIVE TO FIRST DOSE
`
`FIG. 52
`
`36
`T
`
`24
`T
`
`12
`*
`
`1006
`
`1005
`
`1004
`
`*-
`
`1003
`
`1002
`
`1001
`
`0
`
`f
`
`>
`
`0
`10
`20
`30
`40
`50
`60
`70
`80
`
`48
`1
`
`36
`T
`
`24
`T
`
`12
`T
`
`•A • A-
`
`0
`
`50%
`
`60%
`
`70% ^
`
`80%
`
`90%
`
`100% ^
`
`CTC
`
`KPS
`
`OTHER CLINICAL ASSESSMENTS
`
`o>
`to
`w
`9
`C/5 s
`
`H
`M
`
`ffl
`H
`H
`H
`
`CO S z/i
`
`00550
`
`
`
`48
`
`FIG. 53
`WEEKS RELATIVE TO FIRST DOSE
`8
`32
`24
`0
`16
`40
`fhhHHH J
`A •
`•••
`•••i
`,
`,
`,
`lS,CAN
`SCAN
`NORMALIZED
`-LIVER FUNCTION
`
`I
`
`40
`
`36
`
`32
`
`28
`
`24
`
`ULTRASENSITIVE
`
`STANDARD
`
`PSA
`"UNDETECTABLE"
`
`20
`0.0
`
`0.1
`
`0.2
`
`0.3
`
`CHEMO
`TAXOTERE-BASED
`PSA: SUBJECT 1006
`
`PHASE
`INDUCTION
`
`Q
`
`SCAN
`
`-16
`0
`
`PSA, ng/mL
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`to
`w
`
`.r"—>
`
`H
`w
`
`C/5 s
`
`w
`H
`H
`H
`
`CO S z/i
`
`00551
`
`
`
`WO 2011/130566
`
`PCT/US2011/032572
`
`62/72
`
`10,000
`
`1,000
`
`^ '
`
`100
`
`pg/mL
`
`10
`
`1 4
`o
`
`4
`4
`
`2
`
`6
`WEEKS
`
`FIG. 54
`
`uPAR—
`HGF
`
`EGF
`
`^VEGF
`
`4 fr
`8
`
`10
`
`12
`
`SUBSTITUTE SHEET
`
`(RULE
`
`26)
`
`00552
`
`
`
`DETERMINED TMI
`
`NOT
`
`MMD PR
`231%
`
`00
`
`PSA\
`283%
`
`34(W/D)
`SD
`2%
`
`00
`
`PSA\
`-6%
`
`PD
`SD
`47%
`70%
`N/A
`118%
`N/A
`3.7
`66%
`72%
`H
`H
`T. ,2
`1
`1
`2
`2
`1.4
`1.7
`5.0
`7.3
`69.0
`46.5
`312.8
`11.1
`3
`4
`4
`5
`NONE TAXOTER TAXOTER NONE
`9
`10
`8
`7
`80%
`80%
`100%
`90%
`80
`66
`72
`81
`1003
`1004
`1005
`1002
`
`FIG. 55
`
`56+
`SD
`-3%
`298%
`19.5
`-2%
`H
`Tnl
`1
`4.9
`5.8
`4
`NONE
`
`N/A
`
`90%
`73
`1001
`
` MEAN POST-DOSE HYPOXIC CHANGE
`
`RESPONSE
`CLINICAL
`
`RESPONSE
`BIOMARKER
`
`RESPONSE
`IMMUNE
`SAFETY
`
`(WEEKS FROM BASELINE)
`TIME ON STUDY
`BEST RESPONSE
`
`PSADT INCREASE
` 12 WK POST-TREATMENT PSADT
`
` MEAN POST-DOSE CYTOKINE CHANGE
`
`IMMUNE
`RESPONSE
`Ag-SPECIFIC
`MAX AE GRADE
`
` PRE-TREATMENT PSADT (MONTHS)
`
`BASELINE PSA (ng/mL)
`CLINICAL SUBTYPE
`PRIOR CHEMOTHERAPY
`GLEASON SCORE
`METRICS
`KPS (AT SCREENING)
`& BASELINE
`DEMOGRAPHICS AGE
`SUBJECT#
`
`SAFETY & RESPONSE SUMMARY
`
`to o-,
`w
`£
`
`H
`M
`
`C/5 s
`
`w
`H
`H
`H
`
`CO S z/i
`
`00553
`
`
`
`FIG. 56
`
`52,247%
`
`14,616%
`33%
`NOT DETERMINED
`
`-3%
`H
`T, ,1
`
`818.9
`
`2.4
`1070.0
`26.0
`55.8
`4
`4
`4
`5
`NONE TAXOTER NONE TAXOTER TAXOTER TAXOTER
`8
`9
`8
`10
`8
`100%
`90%
`90%
`80%
`90%
`80
`67
`69
`85
`79
`1007
`1008
`1009
`1010
`1011
`
` MEAN POST-DOSE HYPOXIC CHANGE
`
`RESPONSE
`CLINICAL
`
`(WEEKS FROM BASELINE)
`TIME ON STUDY
`BEST RESPONSE
`
`PSADT INCREASE
` 12 WK POST-TREATMENT PSADT
`
`
` MEAN POST-DOSE CYTOKINE CHANGE
`IMMUNE
`RESPONSE
`ANTIGEN-SPECIFIC
`MAX AE GRADE
`
` PRE-TREATMENT PSADT (MONTHS)
`
`BASELINE PSA (ng/mL)
`CLINICAL SUBTYPE
`PRIOR CHEMOTHERAPY
`GLEASON SCORE
`METRICS
`KPS (AT SCREENING)
`& BASELINE
`DEMOGRAPHICS AGE
`SUBJECT#
`
`RESPONSE
`BIOMARKER
`
`RESPONSE
`IMMUNE
`SAFETY
`
`to
`w
`9
`H
`w
`C/5 S
`w
`H
`H
`H
`
`CO S z/i
`
`SAFETY & RESPONSE SUMMARY
`
`00554
`
`
`
`FIG. 57
`0.25
`9.1
`7.7
`N/A
`1.8
`818.9
`26.0
`55.8
`2.4
`1070.0
`4
`4
`4
`4
`5
`TAXOTERE TAXOTERE TAXOTERE
`(ABIRATERONE) TAXOTERE NONE
`9
`8
`10
`8
`8
`LN BIOPSY
`80%
`90%
`90%
`100%
`90%
`69
`79
`85
`67
`80
`1011
`1010
`1009
`1008
`1007
`1.4
`5.0
`4.9
`1.7
`7.3
`69.0
`46.5
`312.8
`11.1
`5.8
`4
`4
`4
`3
`5
`NONE
`NONE TAXOTERE TAXOTERE
`NONE
`8
`9
`10
`7
`7
`80%
`100%
`80%
`90%
`90%
`66
`81
`80
`72
`73
`1005
`1003
`1004
`1001
`1002
`
`PATIENT DEMOGRAPHICS
`
`
`
` PRE-TREATMENT PSADT (MONTHS)
`BASELINE PSA (ng/mL)
`CLINICAL SUBTYPE
`PRIOR CHEMOTHERAPY
`GLEASON SCORE
`KPS (AT SCREENING)
`AGE
`SUBJECT#
`
`
` PRE-TREATMENT PSADT (MONTHS)
`BASELINE PSA (ng/mL)
`CLINICAL SUBTYPE
`PRIOR CHEMOTHERAPY
`GLEASON SCORE
`KPS (AT SCREENING)
`AGE
`SUBJECT#
`
`to
`w
`9
`C/5 s
`
`H
`M
`
`ffl
`H
`H
`H
`
`CO S z/i
`
`00555
`
`
`
`FIG. 58
`
`SD
`
`KD)—
`PROGRESSED
`h®>
`i PROGRESSED, 90% PSA RESPONSE,
`<9)—
`
`"+3"
`
`INDUCTION MAINTENANCE
`
`LEUKAPHERESIS
`
`WEEK 12 ASSESSMENT
`
`£
`
`WEEK 0
`
`BASELINE SCANS
`
`DOSE ESCALATION L-
`
`KD HHHrirt0 LUNG CR, OTHER SD
`)—S
`z
`K
`
`E
`S
` P
`0
`N
`D
`|
`D
`,
`R
`PROGRESSED
`• DURABLE CR POST CHEMO
`PROGRESSED
`RESPONDING TO CHEMO
`^
`DECEASED
`
`
` LOSS, SYMPTOMS) PROGRESSED (WEIGHT
`
`
` @ END 0F STUDY
`
` | | | |^PR
`PROGRESSING
`STABLE DISEASE
`(WITHDREW)
`*
`$
`PROGRESSING
`j fcdl
`SD @ END OF STUDY
`JAN FEB MAR APR MAY JUN
`JUL AUG SEP OCT NOV DEC
`2010
`
`BPX-101 PHASE l/ll CLINICAL TRIAL STATUS
`
`h®
`
`^0
`
`DOSE ESCALATION
`<D~^
`h
`KD
`
`*
`JUL AUG SEP OCT NOV DEC
`2009
`
`o>
`to
`w
`
`H
`
`05 s w
`
`H m
`H
`H
`
`s z/i
`
`«, <!)
`
`00556
`
`
`
`F/G. 59
`
`II
`
`r
`
`////,,
`
`W
`
`W/A.
`
`fev
`
`to
`w
`
`.r"—>
`
`W//////./,
`
`te-.
`
`m
`
`m
`
`m 1
`I
`
`M
`
`20 WEEKS LATER
`RESPONSE
`
`BASELINE CT SCANS OF LUNGS
`SUBJECT 1008: LUNG COMPLETE
`
`H
`
`C/5 S w
`
`W
`H
`H
`
`CO S z/i
`
`00557
`
`
`
`FIG. 60
`FIRST DOSE
`WEEKS RELATIVE TO
`
`56
`
`48
`
`40
`
`32
`
`24
`
`16
`
`8
`
`0
`
`-8
`
`WITHNEULASTA SUPPORT
`WITHOUT PREDNISONE AND-
`REDUCED TO 20 mg/m2
`CABAZITAXEL-DOSE -
`
`SUBJECT 1011
`
`PSA, ng/mL
`
`to
`W
`
`H
`W
`
`C/5 s
`
`w
`H
`H
`H
`
`CO S z/i
`
`4
`0"'N: —————r
`
`-16
`r
`
`-32
`
`-24
`• *
`
`-40
`0 —
`100
`200
`300
`400
`500
`600
`700
`800
`900
`1,000
`1,100 TAXOTERE—KETOCONAZOLE
`1,200
`
`00558
`
`
`
`FIG. 61
`WEEKS RELATIVE TO FIRST DOSE
`
`0
`*
`
`32
`16
`24
`(UROSEPSIS)
`DIED
`
`8
`
`BONESCAN
`
`-8
`
`-16
`
`-24
`
`-32
`
`-40
`
`BONESCAN
`BASELINE
`/
`
`200 1
`
`0
`100
`
`300
`400
`500
`600
`700
`800
`900
`1,000
`1,100
`1,2
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