KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07K-014/00
A61K-049/22
A61K-047/48
A61K-051/08
C07K-007/08
C07K-014/52
C07K-014/71
A61K-038/00
출원번호
US-0109508
(2013-12-17)
등록번호
US-9446155
(2016-09-20)
발명자
/ 주소
Sato, Aaron K.
Sexton, Daniel J.
Dransfield, Daniel T.
Ladner, Robert Charles
Arbogast, Christophe
Bussat, Philippe
Fan, Hong
Khurana, Sudha
Linder, Karen E.
Marinelli, Edmund R.
Nanjappan, Palaniappa
Nunn, Adrian D.
Pillai, Radhakrishna K.
Pochon, Sibylle
Ramalingam, Kondareddiar
Shrivastava, Ajay
Song, Bo
Swenson, Rolf E.
Von Wronski, Mathew A.
Yan, Feng
출원인 / 주소
Bracco Suisse SA
대리인 / 주소
Pearl Cohen Zedek Latzer Baratz LLP
인용정보
피인용 횟수 :
0인용 특허 :
167
초록▼
The present invention provides polypeptides, peptide dimer, and multimeric complexes comprising at least one binding moiety for KDR or VEGF/KDR complex, which have a variety of uses wherever treating, detecting, isolating or localizing angiogenesis is advantageous. Particularly disclosed are synthet
The present invention provides polypeptides, peptide dimer, and multimeric complexes comprising at least one binding moiety for KDR or VEGF/KDR complex, which have a variety of uses wherever treating, detecting, isolating or localizing angiogenesis is advantageous. Particularly disclosed are synthetic, isolated polypeptides capable of binding KDR or VEGF/KDR complex with high affinity (e.g., having a KD1 μM), and dimer and multimeric constructs comprising these polypeptides.
대표청구항▼
1. A diagnostic imaging agent comprising a detectable label conjugated to at least one polypeptide having the ability to bind to KDR or VEGF/KDR complex, optionally further comprising a linker or spacer between the polypeptide and the detectable label, wherein the polypeptide comprises an amino acid
1. A diagnostic imaging agent comprising a detectable label conjugated to at least one polypeptide having the ability to bind to KDR or VEGF/KDR complex, optionally further comprising a linker or spacer between the polypeptide and the detectable label, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: (SEQ ID NO: 263)AGDSWCSTEYTYCEMIGTGGGK;(SEQ ID NO: 264)AGPKWCEEDWYYCMITGTGGGK;(SEQ ID NO: 265)AGVWECAKTFPFCHWFGTGGGK;(SEQ ID NO: 266)AGWVECWWKSGQCYEFGTGGGK;(SEQ ID NO: 268)AGWIQCNSITGHCTSGGTGGGK;(SEQ ID NO: 269)AGWIECYHPDGICYHFGTGGGK;(SEQ ID NO: 270)AGSDWCRVDWYYCWLMGTGGGK;(SEQ ID NO: 271)AGANWCEEDWYYCFITGTGGGK;(SEQ ID NO: 272)AGANWCEEDWYYCWITGTGGGK;(SEQ ID NO: 273)AGPDWCEEDWYYCWITGTGGGK;(SEQ ID NO: 274)AGSNWCEEDWYYCYITGTGGGK;(SEQ ID NO: 275)AGPDWCAADWYYCYITGTGGGK;(SEQ ID NO: 276)AGPEWCEVDWYYCWLLGTGGGK;(SEQ ID NO: 277)AGPTWCEDDWYYCWLFGTGGGK;(SEQ ID NO: 278)AGSKWCEQDWYYCWLLGTGGGK;(SEQ ID NO: 279)AGRNWCEEDWYYCFITGTGGGK;(SEQ ID NO: 280)AGVNWCEEDWYYCWITGTGGGK;(SEQ ID NO: 281)AGANWCEEDWYYCYITGTGGGK;(SEQ ID NO: 282)AGQAWVECYAETGYCWPRSWGTGGGK;(SEQ ID NO: 283)AGQAWIECYAEDGYCWPRSWGTGGGK;(SEQ ID NO: 284)AGVGWVECYQSTGFCYHSRDGTGGGK;(SEQ ID NO: 285)AGFTWVECHQATGRCVEWTTGTGGGK;(SEQ ID NO: 286)AGDWWVECRVGTGLCYRYDTGTGGGK;(SEQ ID NO: 287)AGDSWVECDAQTGFCYSFLYGTGGGK;(SEQ ID NO: 289)AGERWVECRAETGCYTWVSGTGGGK;(SEQ ID NO: 290)AGGGWVECRAETGHCQEYRLGTGGGK;(SEQ ID NO: 291)AGVAWVECYQTTGKCYTFRGGTGGGK;(SEQ ID NO: 292)AGEGWVECFANTGACFTYPRGTGGGK;(SEQ ID NO: 293)GDYPWCHELSDSVTRFCVPWDPGGGK;(SEQ ID NO: 294)GDSRVCWEDSWGGEVCFRYDPGGGK;(SEQ ID NO: 295)GDDHMCRSPDYQDHVCMYWDPGGGK;(SEQ ID NO: 296)GDPPLCYFVGTQEWHHCNPFDPGGGK;(SEQ ID NO: 297)GDDSYCMMNEKGWWNCYLYDPGGGK;(SEQ ID NO: 298)GDPAQCWESNYQGIFFCDNPDPGGGK;(SEQ ID NO: 299)GDGSWCEMRQDVGKWNCFSDDPGGGK;(SEQ ID NO: 300)GDGWACAKWPWGGEICQPSDPGGGK;(SEQ ID NO: 301)GDPDTCTMWGDSGRWYCFPADPGGGK;(SEQ ID NO: 302)GDNWKCEYTQGYDYTECVYLDPGGGK;(SEQ ID NO: 303)GDNWECGWSNMFQKEFCARPDPGGGK;(SEQ ID NO: 486)GDWWECKREEYRNTTWCAWADPGGGK;(SEQ ID NO: 487)GDSSVCFEYSWGGEVCFRYDPGGGK;(SEQ ID NO: 488)GDSRVCWEYSWGGQICLGYDPGGGK;(SEQ ID NO: 304)AQQVQYQFFLGTPRYEQWDLDKGGK;(SEQ ID NO: 305)AQEPEGYAYWEVITLYHEEDGDGGK;(SEQ ID NO: 306)AQAFPRFGGDDYWIQQYLRYTDGGK;(SEQ ID NO: 307)AQGDYVYWEIIELTGATDHTPPGGK;(SEQ ID NO: 308)AQRGDYQEQYWHQQLVEQLKLLGGK;(SEQ ID NO: 309)AQRSWYLGPPYYEEWDPIPNGGK;(SEQ ID NO: 310)AQDWYYDEILSMADQLRHAFLSGGGK;(SEQ ID NO: 311)AGIDFCKGMAPWLCADMGTGGGK;(SEQ ID NO: 312)AGPWTCWLEDHLACAMLGTGGGK;(SEQ ID NO: 313)AGDWGCSLGNWYWCSTEGTGGGK;(SEQ ID NO: 314)GSDHHCYLHNGQWICYPFAPGGGK;(SEQ ID NO: 315)GSNSHCYIWDGMWLCFPDAPGGGK;(SEQ ID NO: 316)SGRLDCDKVFSGPYGKVCVSYGSGGGK;(SEQ ID NO: 317)SGRLDCDKVFSGPHGKICVNYGSGGGK;(SEQ ID NO: 318)SGRTTCHHQISGPHGKICVNYGSGGGK;(SEQ ID NO: 319)SGAHQCHHWTSGPYGEVCFNYGSGGGK;(SEQ ID NO: 320)AGMPWCVEKDHWDCWWWGTGGGK;(SEQ ID NO: 321)AGPGPCKGYMPHQCWYMGTGGGK;(SEQ ID NO: 322)AGYGPCAEMSPWLCWYPGTGGGK;(SEQ ID NO: 323)AGYGPCKNMPPWMCWHEGTGGGK;(SEQ ID NO: 324)AGGHPCKGMLPHTCWYEGTGGGK;(SEQ ID NO: 325)AQAPAWTFGTNWRSIQRVDSLTGGGGGK;(SEQ ID NO: 326)AQEGWFRNPQEIMGFGDSWDKPGGGGGK;(SEQ ID NO: 330)AQEGWFRNPQEIMGFGDSWDKPGGGK;(SEQ ID NO: 331)AQRGDYQEQYWHQQLVEQLKLLGGGK;(SEQ ID NO: 332)AGWYWCDYYGIGCKWTGGGK;(SEQ ID NO: 333)AGWYWCDYYGIGCKWTGTGGGK;(SEQ ID NO: 334)AQWYYDWFHNQRKPPSDWIDNLGGGK;(SEQ ID NO: 336)WQPCPWESWTFCWDPGGGK;(SEQ ID NO: 337)VCWEDSWGGEVCFRYDPGGGK;(SEQ ID NO: 338)AGPTWCEDDWYYCWLFGTJK;(SEQ ID NO: 340)AQAHMPPWRPVAVDALFDWVEGGGGGK;(SEQ ID NO: 341)AQAHMPPWWPLAVDAQEDWFEGGGGGK;(SEQ ID NO: 342)AQAQMPPWWPLAVDALFDWFEGGGGGK;(SEQ ID NO: 343)AQDWYWREWMPMHAQFLADDWGGGGGK;(SEQ ID NO: 344)AQKKEDAQQWYWTDYVPSYLYRGGGGGK;(SEQ ID NO: 345)AQPVTDWTPHHPKAPDVWLFYTGGGGGK;(SEQ ID NO: 346)AQDALEAPKRDWYYDWFLNHSPGGGGGK;(SEQ ID NO: 347)KWCEEDWYYCMITGTGGGK;(SEQ ID NO: 348)AGPKWCEEDWYYCMIGGGK;(SEQ ID NO: 349)KWCEEDWYYCMIGGGK;(SEQ ID NO: 350)AQPDNWKEFYESGWKYPSLYKPLGGGGGK;(SEQ ID NO: 351)AQMPPGFSYWEQVVLHDDAQVLGGGGGK;(SEQ ID NO: 352)AQARMGDDWEEAPPHEWGWADGGGGGK;(SEQ ID NO: 353)AQPEDSEAWYWLNYRPTMFHQLGGGGGK;(SEQ ID NO: 354)AQSTNGDSFVYWEEVELVDHPGGGGGK;(SEQ ID NO: 355)AQWESDYWDQMRQQLKTAYMKVGGGGGK;(SEQ ID NO: 356)AQDWYYDEILSMADQLRHAFLSGGGGGK;(SEQ ID NO: 368)VCWEDSWGGEVCFGGGK;(SEQ ID NO: 369)GDSRVCWEDSWGGEVCFGGGK;(SEQ ID NO: 371)SRVCWEDSWGGEVCFRYGGGGK;(SEQ ID NO: 372)GDSRVCWEDSWGGEVCFRYGGGK;(SEQ ID NO: 374)GDSRVCWEDSWGGEVCFRYDP;(SEQ ID NO: 504)ERVTTCWPGEYGGVECYSVAY;(SEQ ID NO: 462)DWYYGGGK;(SEQ ID NO: 465)AEDWYYDEILGRGRGGRGG;(SEQ ID NO: 453)AGPTWEEDDWYYKWLFGTGGGK;(SEQ ID NO: 454)AGPTWKEDDWYYEWLFGTGGGK;(SEQ ID NO: 455)AGPTWDprEDDWYYDWLFGTGGGK;(SEQ ID NO: 456)AGPTWDEDDWYYDprWLFGTGGGK;(SEQ ID NO: 457)AGPTWDEDDWYYKWLFGTGGGK;and(SEQ ID NO: 480)AGPTWCEDDWYYCWLFGTGGGGK,wherein J is the spacer or linker group 8-amino-3,6-dioxaoctanoyl. 2. The agent of claim 1, wherein the detectable label is conjugated to a dimeric or multimeric compound comprising two or more polypeptides having the ability to bind KDR or VEGF/KDR complex. 3. The agent of claim 1, wherein the polypeptides comprise amino acid sequences that are independently selected from the group consisting of: (SEQ ID NO: 264)AGPKWCEEDWYYCMITGTGGGK;(SEQ ID NO: 294)GDSRVCWEDSWGGEVCFRYDPGGGK;(SEQ ID NO: 310)AQDWYYDEILSMADQLRHAFLSGGGK;(SEQ ID NO: 277)AGPTWCEDDWYYCWLFGTGGGK;(SEQ ID NO: 286)AGDWWVECRVGTGLCYRYDTGTGGGK;and(SEQ ID NO: 337)VCWEDSWGGEVCFRYDPGGGK. 4. The agent of claim 1, wherein at least one of the polypeptides comprises an amino acid substitution, an amide bond substitution, a D-amino acid substitution, a glycosylated amino acid, a disulfide mimetic substitution, an amino acid translocation, a retro-inverso peptide, a peptoid, a retro-inversopeptoid, or a synthetic peptide and wherein the polypeptide maintains its ability to bind the receptor. 5. The agent of claim 1, wherein at least one of the polypeptides does not include the C terminal GGGK extension in its amino acid sequence. 6. The agent of claim 2, wherein the polypeptides comprise any of the following combinations of amino acid sequences: (SEQ ID NO: 277)AGPTWCEDDWYYCWLFGTGGGKand(SEQ ID NO: 337)VCWEDSWGGEVCFRYDPGGGK;(SEQ ID NO: 277)AGPTWCEDDWYYCWLFGTGGGKand(SEQ ID NO: 294)GDSRVCWEDSWGGEVCFRYDPGGGK;(SEQ ID NO: 264)AGPKWCEEDWYYCMITGTGGGKand(SEQ ID NO: 294)GDSRVCWEDSWGGEVCFRYDPGGGK;or(SEQ ID NO: 310)AQDWYYDEILSMADQLRHAFLSGGGKand(SEQ ID NO: 337)VCWEDSWGGEVCFRYDPGGGK. 7. A diagnostic imaging agent comprising a detectable label conjugated to at least two polypeptides having the ability to bind to KDR or VEGF/KDR complex, wherein the detectable label is conjugated, optionally via a linker or spacer, to a dimer selected from the group consisting of D1, D2, D3, D5, D6, D7, D8, D9, D17, D19, D20, D22, D23, D24, D25, D26, D27, D28, and D31, wherein J is the spacer or linker group 8-amino-3,6-dioxaoctanoyl. 8. The agent of claim 7, wherein the dimer is selected from the group consisting of D5 and D6. 9. The agent of claim 1, wherein the polypeptide is linked to the detectable label via a linker or spacer, optionally selected from the group consisting of a substituted alkyl chain, an unsubstituted alkyl chain, a polyethylene glycol derivative, an amino acid spacer, a sugar, an aliphatic spacer, an aromatic spacer, a lipid molecule, and combinations thereof. 10. The agent of claim 1, wherein the detectable label is selected from the group consisting of a fluorescent compound, an optical dye, a paramagnetic metal ion, a superparamagnetic particle, an ultrasound contrast agent, and a radionuclide. 11. The agent of claim 10, wherein the detectable label comprises one or more paramagnetic metal ions and one or more chelators. 12. The agent of claim 11, wherein the paramagnetic metal atom is selected from the group consisting of: Mn2+, Cu2+, Fe2+, Co2+, Ni2+, Gd3+, Eu3+, Dy3+, Pr3+, Cr3+,Co3+, Fe3+, Ti3+, Tb3+, Nd3+, Sm3+, Ho3+, Er3+, Pa4+ and Eu2+. 13. The agent of claim 12, wherein the paramagnetic metal ion is Gd3+. 14. The agent of claim 10, wherein the detectable label comprises a radionuclide comprising a PET agent. 15. The agent of claim 10, wherein the detectable label comprises one or more diagnostic radionuclides and, optionally, one or more chelators. 16. The agent of claim 15, wherein the diagnostic radionuclide is selected from the group consisting of 64Cu, 67Ga, 68Ga, 99mTc and 111In. 17. The agent of claim 10, wherein the detectable label comprises an ultrasound contrast agent. 18. The agent of claim 10, wherein the detectable label comprises a fluorescent compound. 19. The agent of claim 10, wherein the detectable label comprises an optical dye selected from the group consisting of organic chromophores and fluorophores. 20. A method of imaging at least a portion of a patient comprising administering the agent of claim 1, and imaging at least a portion of the patient using a modality sufficient to detect the detectable label.
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