Biosynthetic oncolytic molecules and uses therefor

• US 20040034193A1
• Filed: 08/28/2002
• Published: 02/19/2004
• Est. Priority Date: 06/13/2001
• Status: Abandoned Application

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Ashkar, Samy, Hikita, Sherry, Dehni, Ghassan
• Application Number:
  US10/220,107
• Publication Number:
  US 20040034193A1
• Time in Patent Office: Days
• US Class Current: 530/350
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Novel biosynthetic oncolytic molecules are provided. The biosynthetic oncolytic molecules include functional domains derived from osteopontin. Preferred biosynthetic oncolytic molecules include an apoptotic domain derived from osteopontin. The oncolytic molecules of the present invention are capable of promoting cellular apoptosis. Accordingly, therapeutic uses are disclosed which feature the biosynthetic oncolytic molecules of the present invention.

Claims

1. A biosynthetic oncolytic molecule comprising an apoptotic component and at least one biomodular component, forming a molecule which promotes apoptosis.

2. The oncolytic molecule of claim 1, wherein the apoptotic component is derived from osteopontin.

3. The oncolytic molecule of claim 1, wherein the apoptotic component is a polypeptide.

4. The oncolytic molecule of claim 3, wherein the apoptotic component comprises an amino acid sequence between 5 and 50 amino acid residues in length and is at least 90% identical amino acid residues 147 to 170 sequence of SEQ ID NO:

1.

5. The oncolytic molecule of claim 3, wherein the apoptotic component comprises residues 147 to 170 of SEQ ID NO:

1.

6. The oncolytic molecule of claim 1, wherein the biomodular component is selected from the group consisting of a signal peptide, a linker domain, a golgi processing domain, a heparin binding domain, and a collagen binding domain.

17. The oncolytic molecule of claim 1, wherein the molecule modulates an apoptotic response selected from the group consisting of modulation of chromatin structure, cell viability, and cell lysis.

18. The oncolytic molecule of claim 1, wherein the molecule enhances an apoptotic response.

19. The oncolytic molecule of claim 18, wherein the apoptotic response is cell lysis.

25. A pharmaceutical composition comprising the oncolytic molecule of claim 1, and a pharmaceutically acceptable carrier.

26. A method of modulating an apoptotic response in a cell comprising contacting the cell with an oncolytic molecule of claim 1 such that an apoptotic response is modulated.

7. A biosynthetic oncolytic molecule comprising an apoptotic component, a first biomodular component and a second biomodular component, forming a molecule which modulates cellular apoptosis.

8. The oncolytic molecule of claim 7, wherein the first and second biomodular components are selected from the group consisting of a signal peptide, a linker domain and a golgi processing domain.

9. The oncolytic molecule of claim 8, further comprising a third biomodular component.

10. The oncolytic molecular of claim 9, wherein the third biomodular component is a heparin binding domain or a collagen binding domain.

11. A biosynthetic oncolytic molecule comprising an apoptotic component, a signal peptide, a linker domain and a golgi processing domain.

12. The oncolytic molecule of claim 11, further comprising a heparin binding domain.

13. The oncolytic molecule of claim 12, further comprising a collagen binding domain.

14. The oncolytic molecule of claim 11, comprising an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:

4, wherein the molecule retains an oncolytic activity.

15. The oncolytic molecule of claim 12, comprising an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:

5, wherein the molecule retains an oncolytic activity.

16. The oncolytic molecule of claim 13, comprising an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:

6, wherein the molecule retains an oncolytic activity

20. An isolated nucleic acid molecule comprising nucleic acid sequences which encode a biosynthetic oncolytic molecule.

21. An expression vector comprising the nucleic acid molecule of claim 20.

22. A host cell comprising the vector of claim 20.

23. A method of producing an oncolytic molecule, comprising culturing the host cell of claim 22 under conditions such that the oncolytic molecule is produced.

24. The method of claim 23, further comprising isolating the oncolytic molecule from the medium or the host cell.

27. The method of claim 27, wherein the cell is present within a subject and the oncolytic molecule is administered to the subject.

28. A therapeutic polypeptide comprising the amino acid sequence of SEQ ID NO:

4.

32. An isolated nucleic acid molecule encoding the therapeutic polypeptide of claim 28.

39. An expression vector comprising the nucleic acid molecule of any one of claims 32-38.

40. A host cell comprising the vector of claim 39.

29. A therapeutic polypeptide comprising the amino acid sequence of SEQ ID NO:

5.

33. An isolated nucleic acid molecule encoding the therapeutic polypeptide of claim 29.

30. A therapeutic polypeptide comprising the amino acid sequence of SEQ ID NO:

6.

34. An isolated nucleic acid molecule encoding the therapeutic polypeptide of claim 30.

31. A therapeutic polypeptide comprising the amino acid sequence of SEQ ID NO:

8.

35. An isolated nucleic acid molecule encoding the therapeutic polypeptide of claim 31.

36. An isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:

7.

37. An isolated nucleic acid molecule comprising nucleotides 1-195 of SEQ ID NO:

7.

38. An isolated nucleic acid molecule comprising nucleotides 1-213 of SEQ ID NO:

7.