Conjugates of therapeutic or cytotoxic agents and biologically active peptides

• US 7,771,727 B2
• Filed: 03/03/2003
• Issued: 08/10/2010
• Est. Priority Date: 03/01/2002
• Status: Expired due to Fees

• Current Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY)
• Original Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY)
• Inventors: Coy, David H., Fuselier, Joseph A.
• Primary Examiner(s): Kosar; Andrew D
• Assistant Examiner(s): Gudibande; Satyanarayana R
• Application Number:
  US10/506,223
• Publication Number:
  US 20060009622A1
• Time in Patent Office: 2,717 Days
• Field of Search: None
• US Class Current: 424/185.1
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention features conjugates of therapeutic or cytotoxic agents and biologically active peptides and methods of use thereof.

Claims

1. A compound represented by the following formula:

15. The compound of claim 1, wherein the R₃ group is used to attach a peptide, protein, or antibody to said compound.

16. The compound of claim 15, wherein R₃ is NH(CH₂)mSH and m=2 to 6, and wherein said peptide, protein, or antibody is attached to said compound by a thiol reaction.

17. The compound of claim 15, wherein R₃ is a benzophenone and said peptide, protein, or antibody is attached to said compound by a photochemical reaction.

18. The compound of claim 17, wherein said benzophenone is p-benzoyl-phenylalanine.

2. A compound represented by the following formula:

3. The compound of claim 2, wherein said hydrophilic spacer sequence is said peptide that increases the hydrophilic biodistribution of said compound.

4. The compound of claim 3, wherein at least one V is a D-amino acid.

5. The compound of claim 3, wherein V is independently D-Ser or L-Ser.

6. The compound of claim 2, wherein said hydrophilic spacer sequence is said hydrophilic polymer.

7. The compound of claim 2, wherein said somatostatin peptide, bombesin peptide, or VIP targets said compound to a cell or tissue in the body of a mammal.

8. The compound of claim 7, wherein said somatostatin peptide, bombesin peptide, or VIP is derived from a phage-display library, or comprises conservative substitutions thereof.

9. The compound of claim 7, wherein said cell or tissue comprises a cancer cell, a white blood cell, cardiac tissue, brain tissue, or a tubercle infected with tuberculosis, or wherein said tissue is a tumor or a proliferative angiogenic blood vessel.

10. The compound of claim 9, wherein said blood vessel is in the eye.

11. The compound of claim 2, wherein Q is said somatostatin peptide.

12. The compound of claim 2, wherein Q is said bombesin peptide.

13. The compound of claim 2, wherein Z is D-Ser-Nle-D-Ser-D-Ser, D-Ser-Lys-D-Ser-D-Ser, D-Ser-Lys-D-Tyr-D-Tyr, D-Ser-Lys-D-Tyr-D-Ser, D-Ser-Ser-D-Lys-D-Ser, D-Ser-Ser-D-Lys-Ser, D-Ser-Nle-D-Tyr-D-Ser, D-Ser-Pal-D-Tyr-D-Ser, D-Ser-Thr-D-Tyr-D-Ser, Lys-D-Ser-D-Ser, Ser-D-Lys-D-Ser, Ser-D-Lys-Ser, Nle-D-Tyr-D-Ser, Lys-D-Tyr-D-Ser, Pal-D-Lys-D-Ser, Thr-D-Tyr-D-Ser, D-Ser-D-Lys, D-Ser-D-Tyr, D-Lys-D-Lys, D-Lys-D-Tyr, D-Tyr-D-Lys, or wherein Z has the formula:

E-F, wherein;

E is D-Lys, D-Tyr, D-Ser, D-4-OH-Pro, L-4-OH-Pro, 3-iodo-D-Tyr, 3-5 diiodo-D-Tyr, 3-astatine-D-Tyr, 3-5 astatine-D-Tyr, 3-bromo-D-Tyr, 3-5 dibromo-D-Tyr, D-Asn, L-Asn, D-Asp, L-Asp, D-Gln, or L-Gln; and

F is D-Lys, D-Tyr, D-Ser, L-Ser, D-4-OH-Pro, L-4-OH-Pro, 3-iodo-D-Tyr, 3-5 diiodo-D-Tyr, 3-astatine-D-Tyr, 3-5 astatine-D-Tyr, 3-bromo-D-Tyr, 3-5 dibromo-D-Tyr, D-Asn, L-Asn, D-Asp, L-Asp, D-Glu, L-Glu, D-Gln, or L-Gln.

14. The compound of claim 2, wherein R comprises 1 to 8 carbon atoms.

19. A method of treating a disease comprising administering to a subject suffering from said disease a therapeutically effective amount of the compound of claim 2, wherein the disease is inflammatory bowel disease, rheumatoid arthritis, acromegaly, tuberculosis, a tumor of the lung, breast, brain, eye, prostate or colon, a tumor of neuroendocrine origin, an angiogenesis disease that causes inappropriate proliferation of blood vessels, retinal macular degeneration or diabetic neuropathy.

20. The compound of claim 2, wherein n=2 or 3.

21. The compound of claim 2 admixed with a pharmaceutically acceptable carrier, excipient, or salt.

22. The compound of claim 2, wherein Q is said VIP.

23. The compound of claim 2, wherein said somatostatin peptide is cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH₂.

24. The compound of claim 2, wherein said cytotoxic agent is camptothecin, said linking peptide is D-Ser-Nle-D-Tyr-D-Ser, said targeting moiety is said somatostatin peptide having the sequence cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH₂, said hydrophilic spacer sequence is omitted, and wherein n=2 and R is N(R₁R₂), wherein R₁ and R₂ are hydrogen and methyl, respectively.

25. The compound of claim 24 admixed with a pharmaceutically acceptable carrier, excipient, or salt.

26. The method of claim 19, wherein said tumor of neuroendocrine origin is carcinoid syndrome.

27. The method of claim 19, comprising administering the compound of claim 25 to said subject.

28. The method of claim 19, wherein said subject is a mammal.

29. The method of claim 28, wherein said mammal is a human.