Alpha polyglutamated pralatrexate and uses thereof

Patent metadata

Field	Value
Publication number	US-11730738-B2
Application number	US-201916967303-A
Country	US
Kind code	B2
Filing date	Feb 7, 2019
Priority date	Feb 7, 2018
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

Abstract

The disclosure relates generally to alpha polyglutamated pralatrexate, formulations containing liposomes filled with alpha polyglutamated pralatrexate, methods of making the alpha polyglutamated pralatrexate and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated pralatrexate and liposome containing formulations to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).

First claim

What is claimed is:

1. A liposomal composition comprising an alpha polyglutamated pralatrexate encapsulated by a liposome, wherein the alpha polyglutamated pralatrexate comprises four or more glutamyl groups having an alpha carboxyl group linkage.

2. The liposomal composition of claim 1 , wherein the alpha polyglutamated pralatrexate contains 4, 5, 6, 4-6, or more than 5, glutamyl groups having an alpha carboxyl group linkage.

3. The liposomal composition of claim 1 , wherein:
(a) each of the glutamyl groups of the polyglutamated pralatrexate has an alpha carboxyl group linkage;
b) at least one of the glutamyl groups of the polyglutamated pralatrexate has a gamma carboxyl group linkage;
c) at least one glutamyl group of the polyglutamated pemetrexed has both an alpha carboxyl group linkage and a gamma carboxyl group linkage.

4. The liposomal composition of claim 1 , wherein:
(a) at least 2 of the glutamyl groups of the alpha polyglutamated pralatrexate are in the L-form,
(b) each of the glutamyl groups of the alpha polyglutamated pralatrexate is in the L-form,
(c) at least 1 of the glutamyl groups of the alpha polyglutamated pralatrexate is in the D-form,
(d) each of the glutamyl groups of the alpha polyglutamated pralatrexate other than the glutamyl group of pralatrexate is in the D-form, or
(e) at least 2 of the glutamyl groups of the alpha polyglutamated pralatrexate are in the L-form and at least 1 of the glutamyl groups is in the D-form.

5. The liposomal composition of claim 1 , wherein the liposome comprises an alpha tetraglutamated pralatrexate.

6. The liposomal composition of claim 1 , wherein the liposome comprises an alpha pentaglutamated pralatrexate.

7. The liposomal composition of claim 1 , wherein the liposome comprises an alpha hexaglutamated pralatrexate.

8. The liposomal composition of claim 1 , wherein the polyglutamate is linear or branched.

9. The liposomal composition of claim 1 , wherein the liposome is pegylated.

10. The liposomal composition of claim 1 , wherein the liposome is not pegylated.

11. The liposomal composition of claim 1 , wherein the liposome has a diameter in the range of 20 nm to 500 nm, 20 nm to 200 nm, or 80 nm to 120 nm.

12. The liposomal composition of claim 1 , wherein the liposome is formed from liposomal components comprising:
at least one of an anionic lipid and a neutral lipid;
at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-maleimide; HSPC; HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide; or
at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-FITC; DSPE-PEG-maleimide; cholesterol; and HSPC.

13. The liposomal composition of claim 12 , wherein one or more liposomal components further comprises at least one steric stabilizer selected from: polyethylene glycol (PEG); poly-L-lysine (PLL); monosialoganglioside (GM1); poly(vinyl pyrrolidone) (PVP); poly(acrylamide) (PAA); poly(2-methyl-2-oxazoline); poly(2-ethyl-2-oxazoline); phosphatidyl polyglycerol; poly[N-(2-hydroxypropyl) methacrylamide]; amphiphilic poly-N-vinylpyrrolidones; L amino-acid-based polymer; oligoglycerol, copolymer containing polyethylene glycol and polypropylene oxide, Poloxamer 188, and polyvinyl alcohol.

14. The liposomal composition of claim 13 , wherein the steric stabilizer is PEG and the PEG has a number average molecular weight (Mn) of 200 to 5000 daltons.

15. The liposomal composition of claim 1 , wherein the liposome is anionic or neutral.

16. The liposomal composition of claim 1 , wherein the liposome has a zeta potential that is less than or equal to zero, between 0 to −150 mV, or between −30 to −50 mV.

17. The liposomal composition of claim 1 , wherein the liposome is cationic.

18. The liposomal composition of claim 1 , wherein the liposome has an interior space comprising the alpha polyglutamated pralatrexate and an aqueous pharmaceutically acceptable carrier comprising:
a tonicity agent at a concentration of greater than 1%;
1% to 50% trehalose;
1% to 50% dextrose;
5% dextrose suspended in an HEPES buffered solution; or
a total concentration of sodium acetate and calcium acetate of between 50 mM to 500 mM.

19. The liposomal composition of claim 18 , wherein the interior space of the liposome has a pH of 5-8 or a pH of 6-7, or any range therein between.

20. The liposomal composition of claim 1 , wherein the liposome comprises less than 500,000, less than 200,000, or between 10 to 100,000 molecules of the alpha polyglutamated pralatrexate, or any range therein between.

21. The liposomal composition of claim 1 , which further comprises a targeting moiety and wherein the targeting moiety has a specific affinity for a surface antigen on a target cell of interest.

22. The liposomal composition of claim 21 , wherein the targeting moiety is attached to one or both of a PEG and the exterior of the liposome, optionally wherein targeting moiety is attached to one or both of the PEG and the exterior of the liposome by a covalent bond.

23. The liposomal composition of claim 21 , wherein the targeting moiety is a polypeptide, an antibody or an antigen binding fragment of an antibody.

24. The liposomal composition of claim 21 , wherein the targeting moiety binds the surface antigen with an equilibrium dissociation constant (Kd) in a range of 0.5×10 −10 to 10×10 −6 as determined using surface plasmon resonance analysis.

25. The liposomal composition of claim 21 , wherein the targeting moiety specifically binds one or more folate receptors selected from: folate receptor alpha (FR-α), folate receptor beta (FR-β), and folate receptor delta (FR-δ).

26. The liposomal composition of claim 21 , wherein the targeting moiety comprises one or more selected from: an antibody, a humanized antibody, an antigen binding fragment of an antibody, a single chain antibody, a single-domain antibody, a bi-specific antibody, a synthetic antibody, a pegylated antibody, and a multimeric antibody.

27. The liposomal composition of claim 9 , wherein the pegylated liposome comprises from 1 to 1000 or 30-200 targeting moieties.

28. The liposomal composition of claim 9 , further comprising one or more of an immunostimulatory agent, a detectable marker and a maleimide, wherein the immunostimulatory agent, the detectable marker or the maleimide is attached to said PEG or the exterior of the liposome.

29. The liposomal composition of claim 28 , wherein the immunostimulatory agent is at least one selected from: a fluorescein; a fluorescein isothiocyanate (FITC); a DNP; a beta glucan; a beta-1,3-glucan; a beta-1,6-glucan; a resolvin; a Toll-like receptor (TLR) modulating agent, and an eritoran lipid.

30. The liposomal composition of claim 1 , which further comprises at least one cryoprotectant selected from mannitol; trehalose; sorbitol; and sucrose.

31. The liposomal composition of claim 1 , which further comprises carboplatin and/or pembroluzumab.

32. A pharmaceutical composition comprising the liposomal composition of claim 1 .

33. A method for treating or preventing disease in a subject needing such treatment or prevention, the method comprising administering the liposomal composition of claim 1 to the subject.

34. A method of killing a hyperproliferative cell that comprises contacting a hyperproliferative cell with

Assignees

• L E A F Holdings Group Llc

Inventors

• Niyikiza Clet
• Moyo Victor Mandla

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K47/26

  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 title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title