IP Library › Granted Patent US 8,642,010

Granted Patent B2

US 8,642,010 · App. 12/480,578 · Granted Feb 4, 2014

KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy

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Quick Facts

Patent No.: US 8,642,010
App. No.: 12/480,578
Granted: Feb 4, 2014
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

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 K D <1 μM), and dimer and multimeric constructs comprising these polypeptides.

Claims (513)

1. An ultrasound contrast agent comprising a microvesicle conjugated to at least one polypeptide having the ability to bind to KDR or VEGF/KDR complex, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of

AGDSWCSTEYTYCEMIGTGGGK;

(SEQ ID NO: 263)

AGPKWCEEDWYYCMITGTGGGK;

(SEQ ID NO: 264)

AGVWECAKTFPFCHWFGTGGGK;

(SEQ ID NO: 265)

AGWVECWWKSGQCYEFGTGGGK;

(SEQ ID NO: 266)

AGWIQCNSITGHCTSGGTGGGK;

(SEQ ID NO: 268)

AGWIECYHPDGICYHFGTGGGK;

(SEQ ID NO: 269)

AGSDWCRVDWYYCWLMGTGGGK;

(SEQ ID NO: 270)

AGANWCEEDWYYCFITGTGGGK;

(SEQ ID NO: 271)

AGANWCEEDWYYCWITGTGGGK;

(SEQ ID NO: 272)

AGPDWCEEDWYYCWITGTGGGK;

(SEQ ID NO: 273)

AGSNWCEEDWYYCYITGTGGGK;

(SEQ ID NO: 274)

AGPDWCAADWYYCYITGTGGGK;

(SEQ ID NO: 275)

AGPEWCEVDWYYCWLLGTGGGK;

(SEQ ID NO: 276)

AGPTWCEDDWYYCWLFGTGGGK;

(SEQ ID NO: 277)

AGSKWCEQDWYYCWLLGTGGGK;

(SEQ ID NO: 278)

AGRNWCEEDWYYCFITGTGGGK;

(SEQ ID NO: 279)

AGVNWCEEDWYYCWITGTGGGK;

(SEQ ID NO: 280)

AGANWCEEDWYYCYITGTGGGK;

(SEQ ID NO: 281)

AGQAWVECYAETGYCWPRSWGTGGGK;

(SEQ ID NO: 282)

AGQAWIECYAEDGYCWPRSWGTGGGK;

(SEQ ID NO: 283)

AGVGWVECYQSTGFCYHSRDGTGGGK;

(SEQ ID NO: 284)

AGFTWVECHQATGRVCVEWTTGTGGGK;

(SEQ ID NO: 285)

AGDWWVECRVGTGLCYRYDTGTGGGK;

(SEQ ID NO: 286)

AGDSWVECDAQTGFCYSFLYGTGGGK;

(SEQ ID NO: 287)

AGERWVECRAETGFCYTWVSGTGGGK;

(SEQ ID NO: 289)

AGGGWVECRAETGHCQEYRLGTGGGK;

(SEQ ID NO: 290)

AGVAWVECYQTTGKCYTFRGGTGGGK;

(SEQ ID NO: 291)

AGEGWVECFANTGACFTYPRGTGGGK;

(SEQ ID NO: 292)

GDYPWCHELSDSVTRFCVPWDPGGGK;

(SEQ ID NO: 293)

GDSRVCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 294)

GDDHMCRSPDYQDHVCMYWDPGGGK;

(SEQ ID NO: 295)

GDPPLCYFVGTQEWHHCNPFDPGGGK;

(SEQ ID NO: 296)

GDDSYCMMNEKGWWNCYLYDPGGGK;

(SEQ ID NO: 297)

GDPAQCWESNYQGIFFCDNPDPGGGK;

(SEQ ID NO: 298)

GDGSWCEMRQDVGKWNCFSDDPGGGK;

(SEQ ID NO: 299)

GDGWACAKWPWGGEICQPSDPGGGK;

(SEQ ID NO: 300)

GDPDTCTMWGDSGRWYCFPADPGGGK;

(SEQ ID NO: 301)

GDNWKCEYTQGYDYTECVYLDPGGGK;

(SEQ ID NO: 302)

GDNWECGWSNMFQKEFCARPDPGGGK;

(SEQ ID NO: 303)

GDWWECKREEYRNTTWCAWADPGGGK;

(SEQ ID NO: 486)

GDSSVCFEYSWGGEVCFRYDPGGGK;

(SEQ ID NO: 487)

GDSRVCWEYSWGGQICLGYDPGGGK;

(SEQ ID NO: 488)

AQQVQYQFFLGTPRYEQWDLDKGGK;

(SEQ ID NO: 304)

AQEPEGYAYWEVITLYHEEDGDGGK;

(SEQ ID NO: 305)

AQAFPRFGGDDYWIQQYLRYTDGGK;

(SEQ ID NO: 306)

AQGDYVYWEIIELTGATDHTPPGGK;

(SEQ ID NO: 307)

AQRGDYQEQYWHQQLVEQLKLLGGK;

(SEQ ID NO: 308)

AQRSWYLGPPYYEEWDPIPNGGK;

(SEQ ID NO: 309)

AQDWYYDEILSMADQLRHAFLSGGGK;

(SEQ ID NO: 310)

AGIDFCKGMAPWLCADMGTGGGK;

(SEQ ID NO: 311)

AGPWTCWLEDHLACAMLGTGGGK;

(SEQ ID NO: 312)

AGDWGCSLGNWYWCSTEGTGGGK;

(SEQ ID NO: 313)

GSDHHCYLHNGQWICYPFAPGGGK;

(SEQ ID NO: 314)

GSNSHCYIWDGMWLCFPDAPGGGK;

(SEQ ID NO: 315)

SGRLDCDKVFSGPYGKVCVSYGSGGGK;

(SEQ ID NO: 316)

SGRLDCDKVFSGPHGKICVNYGSGGGK;

(SEQ ID NO: 317)

SGRTTCHHQISGPHGKICVNYGSGGGK;

(SEQ ID NO: 318)

SGAHQCHHWTSGPYGEVCFNYGSGGGK;

(SEQ ID NO: 319)

AGMPWCVEKDHWDCWWWGTGGGK;

(SEQ ID NO: 320)

AGPGPCKGYMPHQCWYMGTGGGK;

(SEQ ID NO: 321)

AGYGPCAEMSPWLCWYPGTGGGK;

(SEQ ID NO: 322)

AGYGPCKNMPPWMCWHEGTGGGK;

(SEQ ID NO: 323)

AGGHPCKGMLPHTCWYEGTGGGK;

(SEQ ID NO: 324)

AQAPAWTFGTNWRSIQRVDSLTGGGGGK;

(SEQ ID NO: 325)

AQEGWFRNPQEIMGFGDSWDKPGGGGGK;

(SEQ ID NO: 326)

AQEGWFRNPQEIMGFGDSWDKPGGGK;

(SEQ ID NO: 330)

AQRGDYQEQYWHQQLVEQLKLLGGGK;

(SEQ ID NO: 331)

AGWYWCDYYGIGCKWTGGGK;

(SEQ ID NO: 332)

AGWYWCDYYGIGCKWTGTGGGK;

(SEQ ID NO: 333)

AQWYYDWFHNQRKPPSDWIDNLGGGK;

(SEQ ID NO: 334)

WQPCPWESWTFCWDPGGGK;

(SEQ ID NO: 336)

VCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 337)

AGPTWCEDDWYYCWLFGTJK;

(SEQ ID NO: 338)

AQAHMPPWRPVAVDALFDWVEGGGGGK;

(SEQ ID NO: 340)

AQAHMPPWWPLAVDAQEDWFEGGGGGK;

(SEQ ID NO: 341)

AQAQMPPWWPLAVDALFDWFEGGGGGK;

(SEQ ID NO: 342)

AQDWYWREWMPMHAQFLADDWGGGGGK;

(SEQ ID NO: 343)

AQKKEDAQQWYWTDYVPSYLYRGGGGGK;

(SEQ ID NO: 344)

AQPVTDWTPHHPKAPDVWLFYTGGGGGK;

(SEQ ID NO: 345)

AQDALEAPKRDWYYDWFLNHSPGGGGGK;

(SEQ ID NO: 346)

KWCEEDWYYCMITGTGGGK;

(SEQ ID NO: 347)

AGPKWCEEDWYYCMIGGGK;

(SEQ ID NO: 348)

KWCEEDWYYCMIGGGK;

(SEQ ID NO: 349)

AQPDNWKEFYESGWKYPSLYKPLGGGGGK;

(SEQ ID NO: 350)

AQMPPGFSYWEQVVLHDDAQVLGGGGGK;

(SEQ ID NO: 351)

AQARMGDDWEEAPPHEWGWADGGGGGK;

(SEQ ID NO: 352)

AQPEDSEAWYWLNYRPTMFHQLGGGGGK;

(SEQ ID NO: 353)

AQSTNGDSFVYWEEVELVDHPGGGGGK;

(SEQ ID NO: 354)

AQWESDYWDQMRQQLKTAYMKVGGGGGK;

(SEQ ID NO: 355)

AQDWYYDEILSMADQLRHAFLSGGGGGK;

(SEQ ID NO: 356)

VCWEDSWGGEVCFGGGK;

(SEQ ID NO: 368)

GDSRVCWEDSWGGEVCFGGGK;

(SEQ ID NO: 369)

SRVCWEDSWGGEVCFRYGGGGK;

(SEQ ID NO: 371)

GDSRVCWEDSWGGEVCFRYGGGK;

(SEQ ID NO: 372)

GDSRVCWEDSWGGEVCFRYDP;

(SEQ ID NO: 374)

ERVTTCWPGEYGGVECYSVAY;

(SEQ ID NO: 504)

DWYYGGGK;

(SEQ ID NO: 462)

AEDWYYDEILGRGRGGRGG;

(SEQ ID NO: 465)

AGPTWEEDDWYYKWLFGTGGGK;

(SEQ ID NO: 453)

AGPTWKEDDWYYEWLFGTGGGK;

(SEQ ID NO: 454)

AGPTWDprEDDWYYDWLFGTGGGK;

(SEQ ID NO: 455)

AGPTWDEDDWYYDprWLFGTGGGK;

(SEQ ID NO: 456)

AGPTWDEDDWYYKWLFGTGGGK;

(SEQ ID NO: 457)

and

AGPTWCEDDWYYCWLFGTGGGGK.

(SEQ ID NO: 480).

wherein J is the spacer or linker group 8-amino- 3,6-dioxaoctanoyl.

2. The agent of claim 1 , wherein the microvesicle 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 agent comprises two or more polypeptides and wherein the polypeptides have specificity for different epitopes on KDR.

4. The agent of claim 3 , wherein the polypeptides comprise amino acid sequences that are independently selected from the group consisting of:

AGPKWCEEDWYYCMITGTGGGK;

(SEQ ID NO: 264)

GDSRVCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 294)

AQDWYYDEILSMADQLRHAFLSGGGK;

(SEQ ID NO: 310)

AGPTWCEDDWYYCWLFGTGGGK;

(SEQ ID NO: 277)

AGDWWVECRVGTGLCYRYDTGTGGGK;

(SEQ ID NO: 286)

and

VCWEDSWGGEVCFRYDPGGGK.

(SEQ ID NO: 337)

5. 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-inverso peptoid, or a synthetic peptide and wherein the polypeptide maintains its ability to bind the receptor.

6. 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.

7. The agent of claim 4 , wherein the polypeptides comprise any of the following combinations of amino acid sequences:

AGPTWCEDDWYYCWLFGTGGGK

(SEQ ID NO: 277)

and

VCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 337)

AGPTWCEDDWYYCWLFGTGGGK

(SEQ ID NO: 277)

and

GDSRVCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 294)

AGPKWCEEDWYYCMITGTGGGK

(SEQ ID NO: 264)

and

GDSRVCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 294)

AQDWYYDEILSMADQLRHAFLSGGGK

(SEQ ID NO: 310)

and

VCWEDSWGGEVCFRYDPGGGK.

(SEQ ID NO: 337)

8. The agent of claim 1 , wherein the polypeptide comprises an amino acid sequence selected from the group consisting of:

AGPKWCEEDWYYCMITGTGGGK;

(SEQ ID NO: 264)

AGPTWCEDDWYYCWLFGTGGGK;

(SEQ ID NO: 277)

GDSRVCWEDSWGGEVCFRYDPGGGK;

(SEQ ID NO: 294)

AQDWYYDEILSMADQLRHAFLSGGGK;

(SEQ ID NO: 310)

and

VCWEDSWGGEVCFRYDPGGGK.

(SEQ ID NO: 337)

9. An ultrasound contrast agent comprising a microvesicle conjugated to at least two polypeptides having the ability to bind to KDR or VEGF/KDR complex, wherein the microvesicle is conjugated 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 D 31, wherein J is the spacer or linker group 8-amino- 3,6-dioxaoctanoyl.

10. The agent of claim 9 , wherein the dimer is selected from the group consisting of D5and D6.

11. The agent of claim 10 , wherein the dimer is D5.

12. The agent of claim 1 , wherein the polypeptide is linked to the microvesicle via a linker or spacer.

13. The agent of claim 12 , wherein said linker or spacer is 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.

14. The agent of claim 1 , wherein the microvesicle comprises a microvesicle-forming material selected from the group consisting of surfactants, lipids, sphingolipids, oligolipids, phospholipids, proteins, polypeptides, carbohydrates and synthetic or natural polymeric materials.

15. The agent of claim 1 , wherein the microvesicle is selected from the group consisting of a microbubble, a microballoon, a microparticle and a microsphere.

16. The agent of claim 15 , wherein the microbubble comprises a phospholipid.

17. The agent of claim 1 , wherein the microvesicle comprises a biocompatible gas, a mixture of biocompatible gases or a gas precursor.

18. The agent of claim 17 , wherein the gas or gas mixture comprises a fluorinated gas.

19. The agent of claim 17 , wherein the gas or gas mixture comprises at least one gas selected from the group consisting of air; nitrogen; oxygen; carbon dioxide; argon, xenon; krypton; a low molecular weight alkane, cycloalkane, alkene or alkyne; a hyperpolarized gas, SF6, a freon and a perfluorocarbon.

20. The agent of claim 17 , wherein the gas or gas mixture comprises a gas selected from the group consisting of SF 6 , C 3 F 8 , C 4 F 8 , C 4 F 10 , and C 5 F 12 .

21. The agent of claim 1 , further comprising a therapeutic agent.

22. A lyophilized residue for preparing an ultrasound contrast agent wherein said residue comprises a phospholipid and at least one polypeptide comprising 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)

AGERWVECRAETGFCYTWVSGTGGGK;

(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- 3,6dioxaoctanoyl.

23. A method of imaging at least a portion of a patient comprising administering the ultrasound contrast agent of claim 1 , and imaging at least a portion of the patient using ultrasound energy.

24. A method of treating a patient comprising administering the ultrasound contrast agent of claim 21 and applying ultrasound energy to the patient.

25. A method of detecting KDR or VEGF/KDR complex in a subject comprising the steps of:

(a) administering the ultrasound contrast agent of claim 1 ;

(b) detecting the ultrasound contrast agent in the subject.

26. The method of claim 25 , further comprising constructing an image.

27. The agent of claim 4 , 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-inverso peptoid, or a synthetic peptide and wherein the polypeptide maintains its ability to bind the receptor.

28. The agent of claim 4 , wherein at least one of the polypeptides does not include the C terminal GGGK extension in its amino acid sequence.

29. The agent of claim 4 , wherein the polypeptide is linked to the microvesicle via a linker or spacer.

30. The agent of claim 29 , wherein said linker or spacer is 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.

31. The agent of claim 4 , wherein the microvesicle comprises a microvesicle-forming material selected from the group consisting of surfactants, lipids, sphingolipids, oligolipids, phospholipids, proteins, polypeptides, carbohydrates and synthetic or natural polymeric materials.

32. The agent of claim 4 , wherein the microvesicle is selected from the group consisting of a microbubble, a microballoon, a microparticle and a microsphere.

33. The agent of claim 10 , wherein the microvesicle comprises a microvesicle-forming material selected from the group consisting of surfactants, lipids, sphingolipids, oligolipids, phospholipids, proteins, polypeptides, carbohydrates and synthetic or natural polymeric materials.

34. The agent of claim 10 , wherein the microvesicle is selected from the group consisting of a microbubble, a microballoon, a microparticle and a microsphere.

35. The agent of claim 32 , wherein the microbubble comprises a phospholipid.

36. The agent of claim 34 , wherein the microbubble comprises a phospholipid.

37. A method of imaging at least a portion of a patient comprising administering the ultrasound contrast agent of claim 4 and imaging at least a portion of the patient using ultrasound energy.

38. A method of imaging at least a portion of a patient comprising administering the ultrasound contrast agent of claim 10 and imaging at least a portion of the patient using ultrasound energy.

39. A method of detecting KDR or VEGF/KDR complex in a subject comprising the steps of:

(a) administering the ultrasound contrast agent of claim 4 ;

(b) detecting the ultrasound contrast agent in the subject.

40. The method of claim 39 , further comprising constructing an image.

41. A method of detecting KDR or VEGF/KDR complex in a subject comprising the steps of:

(a) administering the ultrasound contrast agent of claim 9 ;

(b) detecting the ultrasound contrast agent in the subject.

42. The method of claim 41 , further comprising constructing an image.

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2021

From: DYAX CORP.

To: TAKEDA PHARMACEUTICAL COMPANY LIMITED

Reel/Frame 056268/0983 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 15, 2010

From: BRACCO INTERNATIONAL B.V.

To: BRACCO SUISSE SA

Reel/Frame 024990/0087 →

CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNMENT RECORDATION PREVIOUSLY RECORDED ON REEL 022918 FRAME 0015. ASSIGNOR(S) HEREBY CONFIRMS THE CORRECT SPELLING OF INVENTOR MATHEW VON WRONSKI'S NAME. Recorded Sep 17, 2009

From: ARBOGAST, CHRISTOPHE; BUSSAT, PHILIPPE; FAN, HONG; KHURANA, SUDHA; LINDER, KAREN E.; MARINELLI, EDMUND R.; NANJAPPAN, PALANIAPPA; NUNN, ADRIAN D.; PILLAI, RADHAKRISHNA; POCHON, SIBYLLE; RAMALINGAM, KONDAREDDIAR; SHRIVASTAVA, AJAY; SONG, BO; SWENSON, ROLF E.; VON WRONSKI, MATHEW A.

To: BRACCO INTERNATIONAL B.V.

Reel/Frame 023246/0181 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 6, 2009

To: BRACCO INTERNATIONAL B.V.

Reel/Frame 022918/0015 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 24, 2009

From: SATO, AARON K.; SEXTON, DANIEL J.; LADNER, ROBERT C.; DRANSFIELD, DANIEL T.

To: DYAX CORP.

Reel/Frame 022869/0732 →