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

Patent metadata

Field	Value
Publication number	US-9408926-B2
Application number	US-201314085645-A
Country	US
Kind code	B2
Filing date	Nov 20, 2013
Priority date	Mar 1, 2002
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention provides polypeptides, peptide dimers, 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, particularly contrast agents. Also provided are methods for monitoring and evaluating the therapeutic effectiveness of treatment protocols for diseases associated with angiogenesis or endothelial cell hyperproliferation, such as cancer, using contrast agents of the invention.

First claim

What is claimed is:

1. A method for adjusting a treatment protocol comprising:
(a) administering an ultrasound contrast agent comprising a KDR binding polypeptide having a sequence 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)

AGPTWCADDWYYCWLFGTGGGK;
(SEQ ID NO: 390)

and

VCWEDSWGGEVCFRYDPGGGK.
(SEQ ID NO: 337)

to a subject with a disorder associated with cell hyperproliferation or angiogenesis;
(b) obtaining an initial image of the subject;
(c) administering a therapeutic agent appropriate for the treatment of the disorder;
(d) obtaining a subsequent image of the subject;
(e) comparing the initial and the subsequent images to evaluate the effectiveness of the therapy;
(f) determining whether the effectiveness of the therapy is adequate; and
(g) if the effectiveness of the therapy is determined not to be adequate, adjusting said treatment protocol, terminating said treatment protocol or administering a different treatment protocol.

2. The method of claim 1 , wherein the disorder is cancer.

3. The method of claim 1 , wherein the ultrasound contrast agent comprises one or more KDR binding dimers selected from the group consisting of: Ac-VCWEDSWGGEVCFRYDPGGGK (SEQ ID NO:337) (JJ-C(═O)(CH 2 ) 3 C(═O)—K—NH(CH 2 ) 4 —(S)—CH((Ac-AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO:277))-NH)CONH 2 )—NH 2 ), a dimer comprising Ac-GDSRVCWEDSWGGEVCFRYDPGGGK (SEQ ID NO:294) and Ac-AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO:277), and Ac-AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO:277){Ac-VCWEDSWGGEVCFRYDPGGGK (SEQ ID NO:337) [JJ-Glut-K(SATA)]-NH 2 }—NH 2 .

4. The method of claim 1 , wherein the ultrasound contrast agent comprises a dimer.

5. The method of claim 3 , wherein the dimer is Ac-VCWEDSWGGEVCFRYDPGGGK (SEQ ID NO:337) (JJ-C(═O)(CH 2 ) 3 C(═O)—K—NH(CH 2 ) 4 —(S)-CH((Ac-AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO:277))-NH)CONH 2 )—NH 2 ).

6. The method of claim 1 , wherein the initial and subsequent images are obtained via diagnostic ultrasound.

7. The method of claim 1 , wherein the therapeutic agent is an anti-cancer agent.

8. The method of claim 7 , wherein the cancer is selected from the group consisting of prostate cancer, mammary cancer, ovarian cancer, liver cancer, colon cancer, renal cancer, bone cancer, bladder cancer, pancreatic cancer, lung cancer, uterine cancer and testicular cancer.

9. The method of claim 2 , wherein comparing the initial and subsequent images to evaluate the effectiveness of therapy comprises comparing the size or vascularity of a tumor shown in the images of the subject.

10. The method of claim 2 , wherein comparing the initial and subsequent images to evaluate the effectiveness of therapy comprises comparing a parameter selected from the group consisting of Imax (maximal peak enhancement values), AUC (area under the curve), WIR (Wash-in-rate), and TTP (Time-to Peak).

11. The method of claim 2 , wherein comparing the initial and subsequent images to evaluate the effectiveness of therapy comprises comparing LPO (late phase opacification).

12. The method of claim 7 , wherein the anti-cancer agent is selected from the group consisting of sunitinib, imatinib, sorafenib and bevacizumab.

13. The method of claim 1 , wherein the ultrasound contrast agent comprises a microvesicle filled with a gas or gas mixture.

14. The method of claim 13 , wherein the ultrasound contrast agent comprises a microbubble filled with a gas or gas mixture.

15. The method of claim 13 , wherein the gas or gas mixture comprises fluorinated gas.

16. The method of claim 14 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 hyperpolarized gas, SF 6 , a freon and a perfluorocarbon.

17. The method of claim 15 wherein the gas comprises SF 6 or C 4 F 10 .

18. The method of claim 14 wherein the gas-filed microbubble comprises at least one phospholipid.

19. The method of claim 18 wherein the phospholipid is selected from DPPE, DSPE and DMPE.

20. The method of claim 18 wherein the phospholipid is a saturated phospholipid.

21. The method of claim 14 , wherein the gas or gas mixture comprises fluorinated gas.

22. The method of claim 5 , wherein comparing the initial and subsequent images to evaluate the effectiveness of therapy comprises comparing a parameter selected from the group consisting of Imax (maximal peak enhancement values), AUC (area under the curve), WIR (Wash-in-rate), and TTP (Time-to Peak).

23. The method of claim 5 , wherein comparing the initial and subsequent images to evaluate the effectiveness of therapy comprises comparing LPO (late phase opacification).

Assignees

• Bracco Suisse Sa

Inventors

• Arbogast Christophe
• Bussat Philippe
• Fan Hong (Helen)
• 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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K49/221 Primary

  characterised by the targeting agent or modifying agent linked to the acoustically-active agent · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• A61K51/088

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• C07K14/71

  for growth factors; for growth regulators · CPC title