Saposin C pharmaceutical compositions and methods of treating cancer

• US 10,682,411 B2
• Filed: 11/02/2018
• Issued: 06/16/2020
• Est. Priority Date: 03/23/2018
• Status: Active Grant

• Current Assignee: Bexion Pharmaceuticals, Inc.
• Original Assignee: Bexion Pharmaceuticals, Inc.
• Inventors: Monson, Ellen K., Wei, Xiaochen, Takigiku, Ray, Cruze, III, Charles A., Wyse, Joseph W.
• Primary Examiner(s): Bradley, Christina
• Application Number:
  US16/179,139
• Publication Number:
  US 20190290764A1
• Time in Patent Office: 592 Days
• Field of Search: None
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C12Q 1/40 involving amylase
• CPC Class Codes: C12Q 2334/22 4-Methylumbelliferyl, i.e. beta-methylumbelliferone, 4MU

Abstract

Disclosed are pharmaceutical compositions containing saposin C and phosphatidylserine that are useful for treating various cancers.

Claims

1. A composition comprising:

a polypeptide comprising the amino acid sequence of SEQ ID NO;

1 with zero to four amino acid insertions, substitutions, or deletions;

a phosphatidylserine lipid;

a buffer at pH 5.0 to 8.0;

trehalose at 1.5 to 9 percent w/w;

t-butyl alcohol at 0 to 35 percent; and

water,

wherein the polypeptide is at a concentration of 0.4 to 5.0 mg/ml, and the molar ratio of the phosphatidylserine lipid to the polypeptide is in the range of 8;

1 to 20;

1.

2. The composition of claim 1, wherein the buffer is tris(hydroxymethyl)aminomethane (Tris) at a concentration of 10 to 50 mM, and the pH of the composition is pH 6.8 to 7.6.

3. The composition of claim 1, wherein the buffer is citrate buffer at a concentration of 10 to 50 mM.

4. The composition of claim 1, wherein the buffer is acetate buffer at a concentration of 10 to 50 mM.

5. The composition of claim 1, wherein the phosphatidylserine lipid is dioleoyl phosphatidylserine (DOPS).

6. The composition of claim 1, wherein the phosphatidylserine lipid comprises one or more of DOPS, dihexanoyl phosphatidylserine lipid, dioctanoyl phosphatidylserine lipid, didecanoyl phosphatidylserine lipid, dilauroyl phosphatidylserine lipid, dimyristoyl phosphatidylserine lipid, dipalmitoyl phosphatidylserine lipid, palmitoyl-oleoyl phosphatidylserine lipid, 1-stearoyl-2-oleoyl phosphatidylserine lipid, or diphytanoyl phosphatidylserine lipid.

7. The composition of claim 1, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1 with one or two amino acid insertions, substitutions, or deletions.

8. The composition of claim 1, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1.

9. The composition of claim 1, wherein the polypeptide'"'"'s amino acid sequence consists of SEQ ID NO:

1.

10. The composition of claim 1, wherein

the polypeptide comprises the sequence of SEQ ID NO:

1 and is at a concentration of 1.9 to 2.5 mg/ml;

the phosphatidylserine lipid is DOPS and is at a concentration of 2.0 to 2.8 mg/ml;

the buffer is Tris at a concentration of 23 to 27 mM;

the trehalose is at a concentration of 4 to 6 percent w/w;

the pH of the composition is in the range of pH 6.8 to 7.6; and

the composition further comprises t-butyl alcohol at a concentration of about 15 to 25 percent w/w.

11. A composition in solid form comprising:

a polypeptide comprising the amino acid sequence of SEQ ID NO;

1 with zero to four amino acid insertions, substitutions, or deletions;

a phosphatidylserine lipid;

a buffer; and

trehalose at 75 to 90 percent w/w,

wherein the polypeptide is at a concentration of 3.2 to 4.4 percent w/w, and the molar ratio of phosphatidylserine lipid to polypeptide is in the range of 8;

1 to 20;

1.

12. The composition of claim 11, wherein the buffer is Tris at 5.6 to 7.6 percent w/w.

13. The composition of claim 11, wherein the buffer is citrate buffer at 9 to 13 percent w/w.

14. The composition of claim 11, wherein the buffer is acetate buffer at 3 to 5 percent w/w.

15. The composition of claim 11, wherein the phosphatidylserine lipid is DOPS.

16. The composition of claim 11, wherein the phosphatidylserine lipid comprises one or more of DOPS, dihexanoyl phosphatidylserine lipid, dioctanoyl phosphatidylserine lipid, didecanoyl phosphatidylserine lipid, dilauroyl phosphatidylserine lipid, dimyristoyl phosphatidylserine lipid, dipalmitoyl phosphatidylserine lipid, palmitoyl-oleoyl phosphatidylserine lipid, 1-stearoyl-2-oleoyl phosphatidylserine lipid, or diphytanoyl phosphatidylserine lipid.

17. The composition of claim 11, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1 with one or two amino acid insertions, substitutions, or deletions.

18. The composition of claim 11, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1.

19. The composition of claim 11, wherein the polypeptide'"'"'s amino acid sequence consists of SEQ ID NO:

1.

20. The composition of claim 11, further comprising t-butyl alcohol in an amount less than 3 percent w/w.

21. The composition of claim 11, wherein

the polypeptide comprises the sequence of SEQ ID NO:

1 and is at a concentration of 3.3 to 4.3 percent w/w;

the phosphatidylserine lipid is DOPS and is at a concentration of 3.4 to 4.8 percent w/w;

the buffer is Tris and is at a concentration of 6.0 to 7.2 percent w/w;

the trehalose is at a concentration of 81 to 87.3 percent w/w; and

the composition further comprises t-butyl alcohol at a concentration of less than 3 percent w/w.

41. A method of treating cancer in a human patient, the method comprising reconstituting the composition of claim 11 in water or saline to produce a reconstituted composition, and intravenously administering a dose of the reconstituted composition to the patient.

22. A pharmaceutical composition comprising:

a polypeptide comprising the amino acid sequence of SEQ ID NO;

1 with zero to four amino acid insertions, substitutions, or deletions;

a phosphatidylserine lipid;

a buffer at pH 5.0 to 8;

trehalose at 1.5 to 9 percent w/v; and

water,

wherein the polypeptide is at a concentration of 0.4 to 5 mg/ml, and the molar ratio of phosphatidylserine lipid to polypeptide is in the range of 8;

1 to 20;

1.

23. The pharmaceutical composition of claim 22, wherein the buffer is Tris at a concentration of 10 to 50 mM, and the pH of the composition is pH 6.8 to 7.6.

24. The pharmaceutical composition of claim 22, wherein the buffer is citrate buffer at a concentration of 10 to 50 mM.

25. The pharmaceutical composition of claim 22, wherein the buffer is acetate buffer at a concentration of 10 to 50 mM.

26. The pharmaceutical composition of claim 22, wherein the phosphatidylserine lipid is DOPS.

27. The pharmaceutical composition of claim 22, wherein the phosphatidylserine lipid comprises one or more of DOPS, dihexanoyl phosphatidylserine lipid, dioctanoyl phosphatidylserine lipid, didecanoyl phosphatidylserine lipid, dilauroyl phosphatidylserine lipid, dimyristoyl phosphatidylserine lipid, dipalmitoyl phosphatidylserine lipid, palmitoyl-oleoyl phosphatidylserine lipid, 1-stearoyl-2-oleoyl phosphatidylserine lipid, or diphytanoyl phosphatidylserine lipid.

28. The pharmaceutical composition of claim 22, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1 with one or two amino acid insertions, substitutions, or deletions.

29. The pharmaceutical composition of claim 22, wherein the polypeptide'"'"'s amino acid sequence comprises SEQ ID NO:

1.

30. The pharmaceutical composition of claim 22, wherein the polypeptide'"'"'s amino acid sequence consists of SEQ ID NO:

1.

31. The pharmaceutical composition of claim 22, further comprising t-butyl alcohol in an amount less than 3 percent.

32. The pharmaceutical composition of claim 22, wherein

the polypeptide comprises the amino acid sequence of SEQ ID NO:

1 and is at a concentration of 1.9 to 2.5 mg/ml;

the phosphatidylserine lipid is DOPS and is at a concentration of 2.0 to 2.8 mg/ml;

the buffer is Tris and is at a concentration of 23 to 27 mM;

the trehalose is at a concentration of 4 to 6 percent w/w;

the pH of the composition is in the range of pH 6.8 to 7.6; and

the composition further comprises t-butyl alcohol in an amount less than 0.5 percent w/w.

33. A method of treating cancer in a human patient, the method comprising administering the composition of claim 22 to the patient.

34. The method of claim 33, wherein the patient has a solid tumor.

35. The method of claim 34, wherein the patient has a glioma or ependymoma.

36. The method of claim 34, wherein the patient has a gastrointestinal cancer.

37. The method of claim 33, wherein the composition is delivered intravenously in a dose ranging from 0.4 mg/kg to 7 mg/kg SapC, and the ratio of SapC to DOPS in the composition is in the range of 1:

8 to 1;

20.

38. The method of claim 33, wherein the composition is delivered intravenously in a dose of 2.3-2.5 mg/kg SapC, and the ratio of SapC to DOPS in the composition is in the range of 1:

11 to 1;

13.

39. The method of claim 37, wherein the composition is administered repeatedly to the patient over at least two cycles, as follows:

Cycle 1;

week 1;

one dose on each of days 1-5;

week 2;

three doses every other day;

weeks 3 and 4;

one dose each week (every 7 (+/−

3) days);

Cycle 2;

one dose during week 5.

40. The method of claim 39, further comprising at least one subsequent cycle, wherein the at least one subsequent cycle comprises:

one dose 28 (+/−

3) days after the most recent prior dose.