(57)【要約】 本発明は、単離された組み換え融合ペプタボディに関し、該
Contents
1.2. 49 2007 527206 A 2007 9 27
3. 0 0 0 0 JP 2007 527206 A 2007 9 27 50 00000000000000000000000000000000000 000 BU DU SEE 1
4. Ilulin structure model led fromother members of family J Ml Model 8 13 1 44 11 11 1 1 11 0000000 1000000000000000 000000000 000 0 0 0 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 0 0 HHHHHHHHHHH HHHHHHHHH Savage et al Biol Chem 247 7612 7621 1972 0 0 a 0 schwanora 0000000000000 0 0 Shoyab et al Science 243 1074 1076 1989
5. 10 20 30 50 4 2007 527206 A 2007 9 27 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
6. 2007 527206 A 2007 9 27 5 10 100 20 100000 30
7. 000 HHHHHHHHHHHH 111111 um 0 HHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHIH 0 000 m 111111 000 LU 000 00000 HHHHHHHHHH 11111 1 LU 1 1 1 1000000000 48 2007 527206 A 2007 9 27
8. native sequence 10 0 0 10000000000000000000 100000000 0 0 Carpenter et al Ann Rev Bioch em 56 881 914 1987 00 00 0 Humphrey et PNAS USA 87 4207 4211 19090011 00000000000 100 0 20 10000000000 0 00 000000 0 1000000000000 000000000 0 0 0 Sema et al PNAS USA 82 6497 6501 1985 Yamamoto et al Nature 319 230 234 1986 100000 HHHHHHHHHHHHH 11 000 00000000000000 00 0 30 0 0 00000 10000 1000000000000 000 Kraus et al Proc Natl Acad Sci US
9. 0 0000000000 00 HHHHHHHHHHHHHHHIH HHHHHHHHHHHHHH HHHHHHHHHHHHHHH HHHHHHHHHHHHHH JU UJU DU UU DDD LU HHHHHHHHHHHH HHHHHHHHHHHHHHHHH 0 HHHHHHHHHHH 1000 0 100000000000000 11111 UU 1 000 0000 0 HHHHHHHHHHH HHHHHHHHHHHHHHH HHHHHHHHHH HHHHHHHHHHHHHHH 0 pp 1000000000 00000 00 0 0 0 0 0 0 0 0 0 0 0 DERE HHHHHHHHHHHHHH 11 UU 1 1 11 UU 00000 IDO 00 00000000 11 UU 111 000000 000 111 1 DD DD 0 10000000000000000 HHHHHHHHHHHHHH 0 0 0 0 0 0 0 0 0 0 0 11111111 0 00000000 HHHHHHHHHHHHHH 11 1 1111 11 1 0 0 101001 IH 111 001000 IH 11 11 0 0000000 111111 0 0 0000000 111 11 111 1 0 000000000000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 JP 2007 527206 A 2007 9 27 45
10. 10000000000000000000000000 L L3 L L3 L3 2005 12 6 47 2007 527206 A 2007 9 27
11. s M z ES nen De ER D 10 20 30 50 37 2007 527206 A 2007 9 27 10 20 38 2007 527206 A 2007 9 27 0000 JUD Figure 2 Figure 1 Amino acid sequence of peptabody Irrelevant reouitrrent of reoeptors MYSFEDLHHHHHHGDLGPQMLRELQETNAALQDVRDYLRQLVREITFLKN apoptosis TVMEC
12. 11111 UU D UD 11 lU 000 HHHHHHHHHHHHH 000 HHHHHHHHHHHHH U UU LU 11111 11 LU 000 1000000000000 HHHHHHHHHHHIH 0 1000000000000 HHHHHHH 0000000000000 10 20 30 50 3 2007 527206 A 2007 9 27 L L3 DI
13. 100 100 100 000 HHHHHHHHHHHHHHHHHHH 46 2007 527206 2007
14. HHHHHHHHHHHHH 0000000000000 00000000 10 20 30 50 JP 2007 527206 A 2007 9 27 25 10 000 20 000 0 100000 0 Osol 1000000 1000000 10000000000000000
15. Irrel evant 0 p 00000 1000000 H Lig p 0000 00 0 HHHHHHHHHHHHIlrrelevantH 00000 10000000000000000000000000000 HHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHH 2 0 88 D DB irrelevanti 100000000
16. 1000 n 50 100 1000 000 JP 2007 527206 A 2007 9 27 15 10 10000 100000 100 10000000 1000000 10000000 incl ude 20 humani zed 30
17. 29 JP 2007 527206 A 2007 9 27 1000000000000 HHHHHHH 11111 11010111
18. 0 0 0 HHHHHHHHHHHHHHHHHH 10000 T 5 n a 2 E 5 2007 527206 A 2007 9 27
19. HHHHHHHHHHHHHHHHHHH Stortelers et al 2002 Biochemstry 41 13 42 43011 0 00000000000000000000000 0000000000 1 L L3 L3 1 E L L3 L3 oa L L3 L3 O L L L3 L3 oa L L3 L3 L L3 L3 oa oa L3 L L3 L3 2007 527206 A 2007 9 27 17 in vi vo
20. 10 2007 527206 A 2007 9 27
21. 50 10000000000000000000000000000000 0000000 6 2007 527206 A 2007 9 27 epi dermal growth f 0 0 0 0 poo Mendel so hn a
22. 27 2007 527206 A 2007 9 27 in vitro oa L1 L3 L3 L1 L3 10 20 30 50 2007 527206 A 2007 9 27 28
23. 1000000000000000000000000 10 000000 20 10000 10000 SS S 0 30 1000 10000000 000000000000000 Sambrook et al Molecular Cloning a Laboratory Manual 2nd Edition 1989 old Spring Harbor Laboratory Press especially Chapters 1 4 and 170 0000 100000000 0 100000000 40 000 100000000 0 10000 10000 0000 00000000 00000000000000 0 0 0 0 00 0 1000000000000000000000000000 0 0 000 000 0 000 50 22 JP 2007 527206 A 2007 9 27 00000 10000000000 HHHHHHHHHHH 0
24. 10 20 30 50 JP 2007 527206 A 2007 9 27 12 10 20 30 50 oo C oO a og oo oo o a oo 4 5 oo R Fi E O E EXE Es E _ oo a oo 3 og T lt oo 2 3 3 oo O p x
25. 7 JP 2007 527206 A 2007 9 27
26. 10 20 30 50 8 2007 527206 A 2007 9 27 B Terski kh et al 1997 Peptabody a new type of hi gh avidity bi ndi ng protein Proc Natl Acad Sc USA 94 5 1663 8 Kaj ava 10 20 oana 000000 000 100000000 HH D HB 0 Houi mel et al 1997 Selection of peptides and synthesis of pentaneric Peptabody mol ecules reacting specifically w ith ErbB 2 receptor Int J Cancer 2001 92 748 755 1000000000000000000000000 1000000000000000000000000 HHHHHHHHHHHHHHHHHH
27. 1000 10 20 100 30 10000000 10000 ref ol di ng 50 100 1000 1000 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
28. Irrel evant 2007 527206 A 2007 9 27 31 HHH in vitro 1000 10000000 20 30 in vitro In vitro In vitro 10000000 100 100000000000000 0000 10000000000000000000 100 100 100 in vitro in vitro 50 100 1000 1000 00000000000 in vitro
29. al Meth Enz 58 44 1979 iochem 102 255 1980 a LT tl L L3 L3 24 JP 2007 527206 A 2007 9
30. 10 20 30 50 2007 527206 A 2007 9 27 30 100 1000 100 10 100 0000000 000000000000000000000000000000 20 100 Y a gt O 5 8 O a o O C gt a E i 5 a 10000000000000000 1000000000000000 in vitro 111 1 1 11 0 50
31. exot oxi Bacillus anthracis 00000000 Shi gella Escheri chi a coli 100000 Bordatella pertussis 1000000000 Pseudomonas aer ugi nosa 000000000 00000 ricin 0000 0000 Lamb et al Eur J Biochem 148 265 270 1985 abrin 01000100 0000000 000000 0 Wod et al Eur J Biochem 198 723 732 1991 saporing 10000000000000 100000 BE B Benatti et al Eur J Bi ochem 183 465 470 1989 p okeweed 100000 1000000000000 1000 00000000000 Kataoka et al Plant Mol Biol 20 879 8 86 1992 gel oningpgggoggoooooo0oo00000000 00 10 000 Nolan et al Gene 134 223 227 193 000000000tric hosant hi n 10000000000 0000 0 0 0 0 0 0 0 Shaw et Gene 97 267 272 1991 00000 100 0000000000000 000000000000 00 0 0000 0000000 0000 00000000000000 0 0 Carsana et al Nucleic Acids Res 16 5491 5502 1988 angi Kurachi et al Biochemstry 24 5494 5499 1985 nevrotoxingooo0o0000000 0
32. oana L1 L3 L3 L3 10 20 30 50 2007 527206 A 2007 9 27 19 CN Y LA a a _ a E a a a 1 C C a
33. HHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1000000 50 10000000000000000000000000 11 DR ER DEAE B 33 2007 527206 A 2007 9 27 Mcrosynth
34. 50 in vi vol 2007 527206 A 2007 9 27 26 10 20 30 1000000 1000000 HHHHHHHHHHHHHHHH 50
35. 0000000 HHHHHHHHHHHH JP 2007 527206 A 2007 9 27 32 10 Apot ech 30 1000 1100000000000 000
36. 2007 527206 A 2007 9 27 35 1000 100000 100 100 00000 10 20 30 irrele 50 vant 36 2007 527206 2007 9 27
37. 000 30 50 100 0000000 00000000000 00000 0000000000 00000 in vitro 2007 527206 A 2007 9 27 14 10 100 100 20 30
38. 10 100 20 30 HHHHHHHHHHHHHH HHHHHHHHHHHHHHH HHHHHHHHHHH in vitro 18 2007 527206 A 2007 9 27 ER ES lusia Psi 23 Pseudop 1 psp ENFNGGCLAGYMRTADGRCKPTF 211111 Sp1 25 Spodoptera Sp1 ENFSGGCVAGYMRTPDGRCKPTFYQ Ac etur 23 Mamestra Mab ENFAAGCATGYQRTADGRCKPTF le Spe ENFAGGCATGYLRTADGRCKPTF 23 Spodoptera UM Us Antheraea Any ENFAGGCATGFMRTADGRCKPTF
39. 15A 54 570000 1000000000000000000000000000000000000000 000000000000000000000000000000000000000 1000000000000000000000000000000000000000 00000000000000000000000000000000000000 000000000000000000000000000000000000000 100000 100 1000 2 2007 527206 A 2007 9 27 1000000000000
40. Irrel evant 1000000000000 Pseudal eti a separate 1000000000000000000000000 oaa L L3 L3 oa a oa oa a oa oa oa oa oa oa oa oa L1 Irrel evant AUN A DI 00000000 00 34 2007 527206 A 2007 9 27 HHHHHHHHHHHHHHHHHHHHHHHHHH
41. 2007 527206 A 2007 9 27 19 UP oA R R FA A QD 2007 527206 2007 527206 43 19 9 27 2007 9 27 51 Int Cl C12N 2006 01 15 00 ZNAA 4B024 CO7K 2006 01 19 00 4BO64 CO7K 2006 01 14 78 4B065 7 2006 01 16 18 4 84 COZ 5107 2006 01 5 107 4HO45 A PASARE 57 21 2006 506445 P2006 506445 71 502129715 86 22 16 4 5 2004 4 5 85 17 12 2 2005 12 2 1005 86 PCT IB2004 001049 XX 7 21 87 w02004 087766 74 100090398 87 16 10 14 2004 10 14 AW APR 31 60 460 490 74 100090387 32 15 4 4 2003 4 4 33 US 74 100090479 72 1299
42. 50 100 0000 HS HI 1000000 100000 1000 1000 se 16 2007 527206 A 2007 9 27 11 000000 012016nb00006 0 U o LJ Lr ell et al 1990 Bi ochem Pharma Canp
43. 5 N r3 E E lt gt noo a oo 3 NEM lt n x 3 _ _ oo as Ep ES 3 3 c ER 27 oo MEA 2548 L ES gt a oo E ucES Oo O oo AMES e 3 oo Se oo m O _ qa O gt 3 2 o oO n 3 3 3 a 3 a gt NEM 3 2 2007 527206 A 2007 9 27 13 secretory 10 in vivo in vitro pr esequence 20 100 100
44. 2007 527206 A 2007 9 27 INTERNATIONAL SEARCH REPORT Intormation on patent Family members Patent document Publication Cited In search report date WO 9318943 A 07 05 1998 AU Agternationat Application No US 6350860 81 26 02 2002 AU US 6348568 B1 19 02 2002 US US US AU AU CA CN EP HR HU 1D JP NO NZ PL TR WO US ZA MO 02066628 US 5571507 29 08 2002 DE BR CA WO EP JP NO us 05 11 1996 AU JP WO 0206469 A 24 01 2002 AU NO 9418345 18 08 1994 US AU MO 182004 001049 Patent family Publication member s date 6909298 A 22 05 1998 9818943 Al 07 05 1998 0938571 Al 01 09 1999 9262598 A 08 03 1999 2297692 Al 25 02 1999 9909055 A2 25 02 1999 1015480 A2 05 07 2000 2003099648 Al 29 05 2003 6258782 10 07 2001 6656906 Bi 02 12 2003 2003186874 Al 02 10 2003 766995 B2 30 10 2003 4194999 A 06 12 1999 2332338 Al 25 11 1999 1310626 T 29 08 2001 1079846 Al 07 03 2001 20000789 Al 30 06 2001 0101826 A2 28 09 2001 29141 A 02 08 2001 2002515449 T 28 05 2002 20005836 A 19 01 2001 508352 A 27 02 2004 344342 Al 05 11 2001 200100163 T2 21 06 2001 9959615 Al 25 11 1999 6562787 Bl 13 05 2003 200006642 A 28
45. Kimura et al Nature 348 257 260 1990 00 Cook et al Mol Cell Biol 11 2547 2557 1 991 I oOo DUO DUO 0000 0000000 Shi ng et al Science 259 1604 1607 1993 0 00000000000000 0 HHHHHHHHHHHHHHHHH Sasada et al Biochem Biophys Res Conmun 190 1173 199311 0 0 D 000000000000 0000 0000 000000 Hi gashi yana et al Science 251 936 939 1991 0 0 0 0 1000000000000 00000000 Toyoda et al J Biol Chem 270 7495 7500 1 995 10000 Komrasaki et al Oncogene 15 2841 2848 1997 0000000000000 0000000 Carraway et al Nature 387 512 516 199771 0 D l 0 U Zh et al Proc Natl Acad Sci 94 9562 9567 1997 1 00 Harari et al Oncogene 18 2681 89 1999 0 0000 0000 00000000000 0000 0 Kannan et al Biol Chem 272 6 3330 3335 1997 10000 anphi regul bet ulin 0 epi regulin 1000000 heregulin 4000000000000 0 shope fi broma growth factor 0000 O Mxom Growth Factor 00000 00000 1000000000000 1000000000000 0 0 000000000000000000 0
46. 15 MCF 7 Control p EGF PARR 00000 Figure 16 Muscle B p IRR 1 25 nM El p EGF 1 25 nM z E E p IRR2 5 nM E p EGF 2 5 nM Figure 18 94 2500 Optimem Epidermoid carcer 2580 OptimemiBreast concer m go ga i v 3 ELM f tri za om om 2h DU 1245 26000 Optimem Prostate cancer UEHUCS2800C OptirremiBlacder concer 2 p I ie E 8 ep FR IM e tom a om m Tie 1 34 28000 cancer 2800C Optime Pela 2 Op RR e 10744 de aper we o pre a m m ma 7 ee To 41 2007 527206 A 2007 9 27 Figure 19h Figure 19a Mr Pia ga as adr 00000 00000 20 Figure 22 DNA Sequence Irrelevant Peptabody ATGTATAGCTTIGAAGATCTGGCTAGCCATCATCATCACCATCATGGAGACCTI GGGCC 5 CGCAGATGCTGCGTGAACT GCAGGAAACCAACGCTGCTCTGCAGGACGTTCGTGACTA e CCTGCGTCAGCTGGTTCGTGAAATCACCTICCTGAAAAACACCGTT ATGGAATGCGAC GCTTGCGGTATGCAGCAGACTAGTCCGCCTACTCCGCCAACTCCGTCTCCGTC CTACTCC GCCAACTCCGTCTCCGAGATCTTAA 108 kDa 14 kDa 55 Protein Sequence Irrelevant Peptabody MYSPEDLASHHHHHHGDLGPQMLRELQETNAALQDVRDYLRQLVREITFLKNTVMECDA CGMQOTSPPTPPTP
47. _ L3 a 1 a Ea _ Of a 3 a a u C a en a a a L3 C O C C a L C a u LJ a So 2 a a O a a ENS NE O O oc E vem C 2 5 OL E 5 TE gt e 2 E C gt u E cx 22 gt ae gt E 20 2007 527206 A 2007 9 27
48. gt UE a yamamai Spe s ENFAVGCTPGYQRTADGRCKPTF ENFAGGCTPGYQRTADGRCKATF Spe 2 ENFAGGCTPGYQRTADGRCKPTF ENFVGGCTPGYQRTADGRCKPTF VVSHFNDCPDSHTQFCFHGTCRFLV 50 w SVRVEQVVKPPQNKTESENTSDKPKRKKK GGKNGKNRRNRKKKNPCNAEFQNFCIHGE CKYIEHLEAVTCKCQQEYFGERCGEK DLQEADLDLLRVTLSSKPQALATPNKEEH Rd GKRKKKGKGLGKKRDPCLRKYKDFCIHGE EGF CKYVKELRAPSCICHPGYHGERCHGLSL DGNSTRSPETNGLLCGDPEENCAATTTQS icd KRKGHFSRCPKQYKHYCIKGRCRFVVAEQ Human TPSCVCDEGYIGARCERVDLFY HBT RKGHFSRCPKQYKHYCIKGRCRFVVAEQ 50 deg Human C TPSCVCDEGYIGARCERVDLFY JE S M Mas 1 Mas ENFAGGCAAGYLRTADGROKPTF 23 Manduca 1 Sexta Mas 2 ENFAGGCATGFLRTADGRCKPTF PP2 Sexta Hev 1 ENFSGGCIPGYMRTADGRCKPTY 23 Heliothis PP1 virescens Hev 2 ENFAGGCIPGYMRTADGRCKPTY 23 Heliothis PP2 virescens Tm 1 ENFSGGCLAGYMRTADGRCKPTFG 2 NN ENFSGGCLAGYMRTADGRCKPTF Trichoplusia 23
49. 000000 0000000 000000000 Rosenberg et al Proc Natl Acad Sci USA 8 6 4460 4464 0 100000000000000 mang o qn m m mE DC D ROUTE De PB D fg Dg Hes 0O00000 00000000000 00000000000 11 1 00 0900000000000 0000010 1000000000000000000000000000000 21 2007 527206 A 2007 9 27
50. GR HJ I E IT LU MG NL PL PT RO SE SI SK TR B CF G3 G CM CA GN Q M SN TD TO AG AL AMAT AZ BA BB BG BWBY BZ CH QJ CZ IK DM LZ EE EG ES Fl H MHR HJID IL IN TS J KZ LG LK LR LS LT LU LV MA D M3 W NO CM PG PL PT RO RU SG SD SE SG SK SL SY TM TN TR TT TZ UA UG US V VG W YU ZA M 72 0 0 0 000000 72 00 0000 000000000000000 00000 72 jols 1000 00 48024 AAO1 All BAO1 BA21 BA61 5 QA06 CA07 DX DAO3 DADO 2 FAO7 FALO G8 GN9 H3 4BO64 AG AG A6 AO2 AIO CO6 CED 48065 26 26 AA90X AA93Y ABO ACI4 24 24 AAO2 AAO6 BAO3 BMA DOO 28212 78262 78272 5 AO BAO BAIS BMI 1 020 DA22 2 DA75 20 EA28 72
51. 0000000 180 10 180 2006 1 18 0000000 HAE I 810 001 OA 00000000 0000000 000000 06 0802 09 05 OF 08 02 OL 0 sjuno2 06 08 02 09 0 OF 02 02 OL 0 sjuno2 102 10 105 101 FL1 H FL1 H 06 08 02 09 05 0 08 02 OF 0 FL1 H 06 03 02 09 0 0 08 02 OF 0 sunog 06 08 02 09 0 07 05 02 0 0 sjuno FL1 H 0000000 a IA 0 0000000000000 00000000 0000000 2007 527206 2007 9 27 51 000000 201 01 HV sUL 20 T TUN t 02 1 092 08 09 02 0 1 gt DE D 0r DL 201 LOL 00 SJuno SJuno 52 2007 527206 A 2007 9 27 00000000 INTERNATIONAL SEARCH REPORT ajernatlonal Application No 182004 001049 A CLASSIFICATION OF SUBJECT MATTER IPC 7 0 19 00 C12N15 62 According to International Patent Classification IPC or to both rational classification and IPC B FIELDS SEARCHED Minimum documentation searched classification system followed by classification symbols IPC 7 CO7K C12N Documentation searched other than minimum documentation to Ihe extent thal such documents are Included in the flekts searched Electronic data base consulted during the international search name of data base and where practical search terms u
52. 00 0 0000000 000 ls 000000000000 11111 1 0111 1000000000000 CI L3 L3 L3 10 20 30 50 23 2007 527206 A 2007 9 27 Dul becco 0 0 0 O 500000000000000000
53. 00000 00 0000000 000000 111 0 0 0 00 0 00000 HHHHH 00 00000000 00 100000000000000000000000 000000000 Mendel sohn J 2002 Targeting the epidermal growth factor receptor for cance therapy J Clin Oncol 20 1S 13S 11 1 11 01 1 0 1 10 1 0 0 1 0000 0000 100000000000000000000000 00000000 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ava
54. 05 2001 10108100 Al 29 08 2002 0207385 A 10 02 2004 2438935 Al 29 08 2002 02066628 A2 29 08 2002 1364030 A2 26 11 2003 2004518442 T 24 06 2004 20033671 A 17 10 2003 2003028001 Al 06 02 2003 3730093 A 13 09 1993 2130182 Al 02 09 1993 0630383 Al 28 12 1994 3507541 24 08 1995 9317038 Al 02 09 1993 7355901 A 30 01 2002 0206469 2 24 01 2002 5512435 A 30 04 1996 6171194 29 08 1994 9418345 Al 18 08 1994 Form PCTASA 210 patent family January 2004 57 JP 2007 527206 A 2007 9 27 51 Int d 1000000000 706 200601 7 06 14485 20601 14 485 1449 200601 14 495 1447 2006 01 14 47 1458 2006 01 00 14 58 475 20601 00 14 475 0000 122 2006 01 22 0000 YH 2006 01 O 1 34 yb 2006 01 1 15 119 2006 01 1 19 va 2006 01 1 21 310 2006 01 5 00 0 2102 2006 01 21 02 3800 2006 01 37 02 3 00 2006 01 35 00 3702 2006 01 35 02 0000 4300 2006 01 43 00 8000 0 AP BWGH LS SD SL SZ TZ UG ZM ZW EX AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ OK EE ES Fl FR
55. A 86 19891 0000 0 0 0 1000000 100000000000000000 0 1000000 0 0 1000000 0000000000000000000 0 00 00000 00 000000 1000000000000 000 000 00 0 0 0 0 Plowman al Proc atl Acad Sci USA 90 1746 17500 19931 40 et al Nature 366 473 4751 19930 0 100000000 00000000000000 0 00000000000 000000000000000 100000000 0 1000000 0000000 Lopez Torrejon et al 2002 Human betace 50 11 2007 527206 A 2007 9 27
56. DACGMQQTSPPTPPTPSPSTPPTPSPRS antiangoganic effect 12151501 on cell prdiferation Amino acid sequence of peptabody MYSFEDLHHHHHHGDLGPQMLRELQETNAALQDVRDYLRQLVREITFLKN TVMECDACGMQQTSPPTPPTPSPSTPPTPSPRSNSDSEGPLSHDGHCLH DGVCMYIEALDKYACNCVVGYIGERCQYRDLKWWELR 0000 0000 Figure 3 Figure 4 En EN ECF DEF pEGF MRR PRR 1 Concentrations 39 2007 527206 A 2007 9 27 0000 0000 Figure 5 Figure 7 431 08 Control p EGF PIRR Arbitrary Unit gt a Figure 8 02 0 DU 145 0 1 1 10 100 log p EGF nM 100 5 8 E p RR 1 25 nM 0 E p EGF 1 25 nM 40 RR25 nM 0000 PRA Figure 6 20 m p EGF 2 5 nM 0 A431 Day 100 2 80 B p RR 1 25 nM 60 B p EGF 1 25 nM 4 B p IRR25 nM 8 p EGF 25 nM 0 Day 00010 00000 9 11 DU 145 LNCaP Control p EGF PIRR Control P EGF 10 Figure 12 LNCaP PC 3 100 2 E p IRR 1 25 nM 2 60 p EGF 1 25 nM 5 p IRR 1 25 nM 40 B p IRR 2 5 nM p EGF 1 25 nM B grEGF25nM Bp RR25nM B p EGF 2 5 nM 00000 Figure 13 Control p EGF P IRR 00000 Figure 14 MCF 7 8 B PRR 1 25 nM Ei p EGF 1 25 nM 5 ap RRZS nM B p EGF 2 5 nM 00000 Figure 17 Muscle Control p EGF p IRR 40 JP 2007 527206 A 2007 9 27 00000
57. H 30 0 10000000000000000000000000 40 0 0 0 0 0 0 000000000 0000 000000 0 0 0 00000000000000000000000000 0 0 000000000000000000 0 00 0 100000000000000000 0000000000000 Har werth et al Monoclonal anti bodies against the extracellular domain of ErbB 2 receptor function as partial ligand agonist Biol Chem 1992 267 15160 7 11 EA 101011 00 000 00000000000000000000000000 0 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1000000000000000000000000000000000000000 50 9 2007 527206 A 2007 9 27 0 0000000
58. IUM KLUWER ACADEMIC PUBLISHERS 3300 AA DORDRECHT NETHERLANDS KLUWER ACADEMIC PUBLISHERS 101 PHILLIP DRIVE ASSINIPPI PARK NORWELL 02061 USA 2000 pages 47 49 XP009034147 amp 16TH AMERICAN PEPTIDE SYMPOSIUM MINNEAPOLIS ME USA JUNE 26 JULY 01 1999 ISSN 0 7923 6445 7 the whole document WO 98 18943 A CIBA GEIGY AG KAJAVA ANDREY CH UNIV LAUSANNE CH CRAMERI RETO 7 May 1998 1998 05 07 the whole document GARIEPY J ET AL Vectorial delivery of macromolecules into cells using peptide based vehicles TRENDS IN BIOTECHNOLOGY ELSEVIER AMSTERDAM GB 19 1 1 January 2001 2001 01 01 pages 21 28 4227647 ISSN 0167 7799 See 1n particular paregraphbridging pages 23 and 24 NOMIZU MOTOYOSHI ET AL Multimeric forms of Tyr Ile Gly Ser Arg YIGSR peptide enhance the inhibition of tumor growth and metastasis CANCER RESEARCH vol 53 no 15 1993 pages 3459 3461 XP001182805 ISSN 0008 5472 the whole document US 6 350 860 Bl SABLON ERWIN AL 26 February 2002 2002 02 26 the whole document US 6 348 568 ANWER MOHMED AL 19 February 2002 2002 02 19 the whole document WO 02 066628 A CAVENTIS PHARMA GMBH 29 August 2002 2002 08 29 the whole document Er um Form POTASA210 continuation of second sheet 2004 55 2007 527206 A 2007 9 27 INTERNATI
59. ONAL SEARCH REPORT atematlonal Application No CT 1B2004 001049 Category Citallon of document with indicalion where appropriale of the relevant passages Relevant o claim No US 5 571 507 A BACH JEAN FRANCOIS ET AL 5 November 1996 1996 11 05 the whole document WO 02 06469 A COCO WAYNE M ENCELL LANCE P 05 ARENSDORF JOSEPH J US ENCHIRA B 24 January 2002 2002 01 24 SEQ ID NO 17 CARAGLIA M ET AL EGF activates an inducible survival response via the RASfwdarwErk 1 2 pathway to counteract interferon alpha mediated apoptosis in 14 cancer cells CELL DEATH AND DIFFERENTIATION vol 10 2 February 2003 2003 02 pages 218 229 XP009034327 ISSN 1350 9047 the whole document MURAYAMA YOICHI High concentration af epidermal growth factor induces apoptosis in breast and esophageal cancer cells transplanted into nude mice ONCOLOGY REPORTS vol 1 no 6 1994 pages 1055 1062 XP009034329 the whole document 94 18345 AFFYMAX TECH UNIY LELAND STANFORD JUNIOR US 18 August 1994 1994 08 18 49 GENNITY J AL SIGNAL PEPTIDE MUTANTS OF ESCHERICHIA COLI JOURNAL OF BIOENERGETICS AND BIOMEMBRANES PLENUM PUBLISHING NEW YORK NY US vol 22 3 June 1990 1990 06 pages 233 269 XP009025834 ISSN 0145 479 the whole document Form POTASA 210 continumlon of second sheet January 2004 56
60. SPSTPPTPSPRS 00000 00000 Figure 23 21 DNA Sequence Peptabody EGF MDP01 ATGTATAGCTTIGAAGATCTGOCTAGCCATCATCATCACCATCATGGAGACCTOGGCO ct CGCAGATGCTGCGTGAACTGCAGGAAACCAACGCTGCTCTGCAGGACGTTCGTGACTA a CCTGCGTCAGCTGGTTCGTGAAATCACCTTCCTGAAAAACACCGTTATGGAATGCGAC GCTTGCGGTATGCAGCAGACTAGTCCGCCTACTCCGCCAACTCCGTCTCCGTCTACTCC DECO GCCAACTCCGTCTCCGAGATCCAATTCTGACTCTGAATGCCCATTGTCTCACGACGG IIACTGCTTGCACGACGGTGTTTGCATGTACATCGAAGCTCTGGACAAATACGCT TGCAACTGCGTTGTTGGTTACATCGGTGAACGTTGCCAATACCGAGATCTGAAAT Protein Sequence Peptabody EGF SFEDLASHEHHHHGDLGPQMLRELQETNAALQDVRDYLRQLVREITFLENTVMECDA Day Day Day CGMQQ TSPPTPPTPSPSTPPTPSPRSNSDSECPLSHDGYCLHDGYCMYIEALDKY ACNC VYGYIGERCOYRDLKWWELR 42 2007 527206 A 2007 9 27 00000 00000 Figure 26 Figure 24 Production of peptabodies fused to different Enhancers DNA Sequence Peptabody GBP ATGGAGACCTGGGCC CGCAGATGCTGCGTGAACTGCAGGAAACCAACGCTGCTCTI GCAGGACGTTCGTGACTA CCTGCGTCAGCTGGTTCGTGAAATCACCTTCCTGAAAAACACCGTTATGGAATGCGAC EnhO GCTTGCGGTATGCAGCAGACTAGTCCGCCTACTCCGCCAACTCCGTCTCCUTCTACTCC Ephl Y 5 F CC44CZCCC7C7CCOAGATCTGAAAACTTTTCCGGCGGCTGCGTGGCGGGCTATA Enh Y 5 TGCGTACCCCGGATGGCCGTTGCAAACCGACCTTTTATCAGTAA Euh3 Y 8 F Enbd Y S F Enh5 8
61. idered to Involve an Inventive step when the document referring 10 an oral disclosure use exhibition or documenti is combined with or more other such docu other means menis such combination being obvious to person skilled document published prior to the internatlonaf filling date but n the art later than the priority date claimed amp document member of the same patent family Date of the actual completion of the international search Date of mailing of the search report 0 17 September 2004 06 10 04 and mailing address of the ISA Authorized officer European Patent Office 5816 Patentlaan 2 NL 2280 HV Rijswijk Tel 31 70 340 2040 Tx 31 651 epo nl Fax 31 70 340 3016 Valcarcel Form PCTASA 210 eacond sheat Jenuery 2004 53 2007 527206 A 2007 9 27 daernational Application No 182004 001049 Relevant to claim INTERNATIONAL SEARCH REPORT Continuatlon DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document wih indication where appropriate of the relevant passages DEPERTHES DAVID LUC ET AL Effect of peptabody anti Epidermal Growth Factor receptors on prostate cancer cell lines proliferation EUROPEAN UROLOGY SUPPLEMENTS vol 1 no 1 January 2002 2002 01 page 31 XP009034146 amp XVIITH CONGRESS OF THE EUROPEAN ASSOCIATION OF UROLOGY BIRMINGHAM ENGLAND UK FEBRUARY 23 26 2002 ISSN 1569 9056
62. p E Enb 6 p E p Protein Sequence Peptabody GBP MDP03 Enh E D X MY SFEDLASHHHHHHGDLGPOMLRELQETNAALQDVRDYLRQLVREITFLENTVMECDA CGMOQTSPPTPPTPSPSTPPTPSPRSE NFSGGCVAGYMRTPDGRCKPTFYQ 00000 Figure 25 Production ef decabadies fused ta different Enhancers Enho Enhi YSFEDL YSPEDLYERR 1 TD peptide SINHNR 00000 27 PIS tae RBS 44 43 2007 527206 A 2007 9 27 06000001 170 20 80 2005 2 8
63. sed EPO Internal 0515 WPI Data PAJ EMBASE CHEM ABS Data DOCUMENTS CONSIDERED TO RELEVANT Category Citation of document with indication where appropriste of ihe relevant passages Relevant to claim No HOUIMEL MEHDI ET AL Selection of peptides and synthesis of pentameric peptabody malecules reacting specifically with ErbB 2 receptor INTERNATIONAL JOURNAL OF CANCER vol 92 no 5 1 June 2001 2001 06 01 pages 748 755 XP009034136 ISSN 0020 7136 the whole document x Further documents are listed in the continuation of box C k Palem family members are listed in annex Special categories of cited documents later document published amor na filing date ane n 2 or priority date and not in conilict with the application but document defining the general state ofthe art which s not considered to be of particular relevan cited to understand the principle or theory underlying the Invention earlier document but published or afterihe intemationai X document of panicular relevance the claimed invention filing date cannot be considered novel or cannot be considered to flocument throw Let on pony or involve step when the document is taken alone which to esapish me pu lication date of another document of parlicufar relevance the claimed invention citation or olher special reason as specified cannot be cons
64. the whole document CAMPBELL I D ET AL STRUCTURE FUNCTION RELATIONSHIPS IN EPIDERMAL GROWTH FACTOR EGF AND TRANSFORMING GROWTH FACTOR ALPHA TGF ALPHA BIOCHEMICAL PHARMACOLOGY vol 40 no 1 1990 pages 35 40 XP002289670 amp FOURTH BIOCHEMICAL PHARMACOLOGY SYMPOSIUM ON NMR METHODS FOR ELUCIDATING MACROMOLECULE LIGAND INTERA ISSN 0006 2952 Cited in the application the whole document STORTELERS CATELIJNE AL Epidermal growth factor contains both positive and negative determinants for interaction with ErbB 2 ErbB 3 heterodimers BIOCHEMISTRY vol 41 no 13 2 April 2002 2002 04 02 pages 4292 4301 XP002289671 ISSN 0006 2960 Cited in the application the whole document LEHTO EGF receptor which way to go FEBS LETTERS ELSEVIER SCIENCE PUBLISHERS AMSTERDAM NL vol 491 no 1 2 23 February 2001 2001 02 23 pages 1 3 XP004257261 ISSN 0014 5793 page 2 Forn PCTASA 210 continuation of second sheet January 2004 54 2007 527206 A 2007 9 27 INTERNATIONAL SEARCH REPORT International Application Na 182004 001049 Continuation DOCUMENTS CONSIDERED BE RELEVANT Citation of document with indication where appropriate of the relevant passages Relevant to claim No ROSE KEITH ET AL Polyethyleneglycol based chains of precise length for chemabodies PEPTIDES FOR THE NEW MILLENN
65. transforming gro weh factor alpha TGF al pha 10000 Coussens et al Science 230 1985 1132 1139 et al Nature 319 1986 230 2347 00000000 00000000 000000000080 L3 L3 00000 Boe 1 10 0 0 Kraus et al Proc Natl Acad Sci USA 86 1989 0 000 PI owman et al Proc Natl Acad Sci USA 87 1990 4905 4909 10000 00 100 100 U 0 10000 U U 100 U k BB FR D P tl FJ i Pl owran et a l Proc Natl Acad Sci USA 90 1993 1746 17500 LU HM HM lt
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