Alpha polyglutamated antifolates and uses thereof

Patent metadata

Field	Value
Publication number	US-12076402-B2
Application number	US-201916967213-A
Country	US
Kind code	B2
Filing date	Feb 7, 2019
Priority date	Feb 7, 2018
Publication date	Sep 3, 2024
Grant date	Sep 3, 2024

Abstract

The disclosure relates generally to alpha polyglutamated Antifolates, formulations containing liposomes filled with alpha polyglutamated Antifolates, methods of making the alpha polyglutamated Antifolates and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated Antifolates 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 Antifolate encapsulated by a liposome, wherein the polyglutamated antifolate comprises at least 4 glutamate residues and wherein at least 2 of the glutamate residues contain an alpha carboxyl group linkage and are in the L-form or D-form.

2. The liposomal composition of claim 1 , wherein the Antifolate is selected from: pemetrexed (PMX), methotrexate (MTX), raltitrexed (RTX), and lometrexol (LMX), or a stereoisomer thereof.

3. The liposomal composition of claim 1 , wherein the Antifolate is selected from: piritrexim, pralatrexate, AG2034, GW1843, and LY309887, or a stereoisomer thereof; LV (etoposide), L-leucovorin (L-5-formyltetrahydrofolate); 5-CH3-THF, 5-methyltetrahydrofolate; FA, folic acid; PteGlu, pteroyl glutamate (FA); 2-dMTX, 2-desamino-MTX; 2-CH3-MTX, 2-desamino-2-methyl-MTX; AMT, aminopterin; 2-dAMT, 2-desamino-AMT; 2-CH3-AMT, 2-desamino-2-methyl-AMT; 10-EdAM, 10-ethyl-10-deazaaminopterin; PT523, N alpha -(4-amino-4-deoxypteroyl)-N delta-(hemiphthaloyl)-L-ornithine; DDATHF (lometrexol), 5,10-dideaza-5,6,7,8, -tetrahydrofolic acid; 5-d(i)H4PteGlu, 5-deaza-5,6,7,8-tetrahydroisofolic acid; N9-CH3-5-d(i)H4PteGlu, N9-methyl-5-deaza-5,6,7,8-tetrahydroisofolic acid; 5-dPteHCysA, N alpha -(5-deazapteroyl)-L-homocysteic acid; 5-dPteAPBA, N alpha -(5-deazapteroyl)-DL-2-amino-4-phosphonobutanoic acid; 5-dPteOrn, N alpha -(5-deazapteroyl)-L-ornithine; 5-dH4PteHCysA, N alpha -(5-deaza-5,6,7,8-tetrahydropteroyl)-L-homocysteic acid; 5-dH4PteAPBA, N alpha -(5-deaza-5,6,7,8-tetrahydropteroyl)-DL-2-amino-4-phosphobutanoic acid; 5-dH4PteOro, N alpha -(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine; CB3717, N10-propargyl-5,8-dideazafolic acid; ICI-198,583, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid; 4-H-ICI-198,583, 4-deoxy-ICI-198,583: 4-OCH3-ICI-198,583, 4-methoxy-ICI-198,583 Glu-to-Val-ICI-198,583; valine-ICI-198;583; Glu-to-Sub-ICI-198,583, 2-amino-suberate-ICI-198,583; 7-CH3-ICI-198,583, 7-methyl-ICI-198,583; ZD1694, N-[5(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl-methyl)amino)2-thienyl)]-L-glutamic acid; 2-NH2-ZD1694, 2-amino-ZD1694; BW1843U89, (S)-2[5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino-)-1-oxo-2-isoindolinyl]-glutaric acid; LY231514, N-(4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-D]pyrimidin-5-yl)ethyl)-benzoyl]-L-glutamic acid; IAHQ, 5,8-dideazaisofolic acid; 2-dIAHQ, 2-desamino-IAHQ; 2-CH3-dIAHQ, 2-desamino-2-methyl-IAHQ; 5-d(i)PteGlu, 5-deazaaisofolic acid; N9-CH3-5-d(i)PteGlu, N9-methyl-5-deazaisofolic acid; N9-CHO-5-d(i)PteGlu, N9-formyl-5-deazaisofolic acid; AG337, 3,4-dihydro-2-amino-6-methly-4-oxo-5-(4-pyridylthio)quanazoline; and 2,4-diamino-6[N-(4-(phenylsulfonyl)benzyl)ethyl)amino]quinazoline; or a stereoisomer thereof; and methotrexate, raltitrexed, plevitrexed, pemetrexed, lometrexol (LMX; 5,10-dideazatetragydrofolic acid), a cyclopenta[g]quinazoline with a dipeptide ligand, CB3717, CB300945, or a stereoisomer thereof.

4. The liposomal composition of claim 1 , wherein,
(a) each of the glutamyl groups of the polyglutamated Antifolate other than the glutamyl group of the Antifolate has an alpha carboxyl group linkage;
(b) two or more glutamyl groups of the polyglutamated Antifolate have a gamma carboxyl group linkage;
(c) each of the glutamyl groups other than the C-terminal glutamyl group or groups and the glutamyl group of the Antifolate has an alpha carboxyl group linkage; or
(d) each of the glutamyl groups other than the C-terminal glutamyl group or groups has an alpha carboxyl group linkage.

5. The liposomal composition of claim 1 , wherein the alpha polyglutamated Antifolate comprises 2-10 glutamyl groups having an alpha carboxyl group linkage.

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

7. The liposomal composition of claim 1 , wherein the liposome comprises an alpha polyglutamated Antifolate containing 4, 5, 6, 2-10, 4-6, or more than 5, glutamyl groups.

8. The liposomal composition of claim 1 , wherein the liposome comprises an alpha tetraglutamated Antifolate.

9. The liposomal composition of claim 1 , wherein the liposome comprises an alpha pentaglutamated Antifolate.

10. The liposomal composition of claim 1 , wherein the liposome comprises an alpha hexaglutamated Antifolate.

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

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

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

14. 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.

15. 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: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); DSPE-polyethylene glycol (PEG); DSPE-PEG-maleimide; hydrogenated soy L-a-phosphatidylcholine (HSPC); HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide; or
at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-fluorescein isothiocyanate (FITC); DSPE-PEG-maleimide; cholesterol; and HSPC.

16. The liposomal composition of claim 1 , 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.

17. The liposomal composition according to claim 16 , wherein the steric stabilizer is polyethylene glycol (PEG) and the PEG has a number average molecular weight (Mn) of 200 to 5000 daltons.

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

19. The liposomal composition of claim 18 , 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.

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

21. The liposomal composition of claim 1 , wherein the liposome has an interior space comprising the alpha polyglutamated Antifolate 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 (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffered solution; or
a total concentration of sodium acetate and calcium acetate of between 50 mM to 500 mM.

22. The liposomal composition of claim 21 , wherein the phar

Assignees

• L E A F Holdings Group Llc

Inventors

• Niyikiza Clet
• Moyo Victor Mandla

Classifications

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6913

  the liposome being modified on its surface by an antibody · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title