# US 2025/0082575 A1 · Gamma polyglutamated pralatrexate and uses thereof

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- Number: US 2025/0082575 A1
- Document ID: US20250082575A1
- Status: Published application
- Kind: A1
- Application number: 18/745,801
- Filed: 2024-06-17
- Published: 2025-03-13
- Earliest claimed: 2018-02-14
- Assignees: L.E.A.F. Holdings Group LLC
- Applicants: L.E.A.F. Holdings Group LLC
- Inventors: Clet NIYIKIZA; Victor Mandla MOYO
- Web page: https://patentgrep.com/patent/US20250082575A1

## CPC

- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 47/6913: {the liposome being modified on its surface by an antibody}
- A61K 9/1277: Preparation processes; Proliposomes
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- 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
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61P 35/00: Antineoplastic agents
- C07D 475/04: with a nitrogen atom directly attached in position 2
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2818: {against CD28 or CD152}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The disclosure relates generally to gamma polyglutamated pralatrexate compositions, including delivery vehicles such as liposomes containing the gamma polyglutamated pralatrexate, and methods of making and using the gamma polyglutamated pralatrexate compositions to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., inflammation and autoimmune diseases such as rheumatoid arthritis).

## Claims

### Claim at position 1

1-94. (canceled)

### Claim 95

A liposomal composition comprising a gamma polyglutamated pralatrexate encapsulated by a liposome, wherein the polyglutamated pralatrexate has 4, 5, 2-10, 4-6, or more than 5, glutamyl groups in the D-form having gamma carboxyl group linkages,
wherein the liposome is pegylated and does not contain a targeting moiety having specific affinity for a surface antigen on a target cell,
wherein the liposome does not contain a cell penetrating peptide and does not contain a mitochondria penetrating agent,
wherein the liposome has a zeta potential that is less than or equal to zero, between 0 and −150 mV, or between −30 and −50 mV, and
wherein the liposome is capable of delivering the gamma polyglutamated pralatrexate directly into a cell.

### Claim 96 (depends on 95)

The liposomal composition of claim 95, wherein the liposome further comprises one or more nonpolyglutamated polyglutamatable antifolate or non-polyglutamatable antifolate.

### Claim 97 (depends on 95)

The liposomal composition of claim 95, wherein the gamma polyglutamated pralatrexate has 4, 5, 2-10, or 4-6 glutamyl groups in the D-form.

### Claim 98 (depends on 95)

The liposomal composition of claim 95, wherein the gamma polyglutamated pralatrexate comprises gamma tetraglutamated pralatrexate.

### Claim 99 (depends on 95)

The liposomal composition of claim 95, wherein the gamma polyglutamated pralatrexate comprises gamma pentaglutamted pralatrexate.

### Claim 100 (depends on 95)

The liposomal composition of claim 95, wherein the gamma polyglutamated pralatrexate comprises gamma hexaglutamted pralatrexate.

### Claim 101 (depends on 95)

The liposomal composition of claim 95, 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.

### Claim 102 (depends on 95)

The liposomal composition of claim 95, wherein the liposome is formed from liposomal components comprising:
at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-maleimide; HSPC; HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide.

### Claim 103 (depends on 102)

The liposomal composition of claim 102, wherein the liposome is further comprised of at least one steric stabilizer selected from: 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.

### Claim 104 (depends on 95)

The liposomal composition of claim 95, wherein the liposome comprises between 10 and 500,000, between 10 and 200,000, or between 10 to 100,000 molecules of the gamma polyglutamated pralatrexate, or any range therein between.

### Claim 105 (depends on 95)

The liposomal composition of claim 95, which further comprises at least one cryoprotectant selected from mannitol, trehalose, sorbitol, and sucrose.

### Claim 106 (depends on 95)

The liposomal composition of claim 95, which further comprises carboplatin or pembrolizumab.

### Claim 107 (depends on 96)

The liposomal composition of claim 96, wherein the nonpolyglutamated polyglutamatable antifolate is selected from: methotrexate (MTX), pemetrexed (PMX), lometrexol (LMX), raltitrexed (RTX), pralatrexate, AG2034, GW1843, aminopterin, and LY309887; or the non-polyglutamatable antifolate is selected from: trimetrexate (TMQ), piritrexim (BW301U), and talotrexin (PT523), nolatrexed (AG337), plevitrexed, and BGC 945 (ONX 0801).

### Claim 108 (depends on 95)

The liposomal composition of claim 95, wherein the polyglutamated pralatrexate has 2-10 glutamyl groups in the D-form having gamma carboxyl group linkages.

### Claim 109 (depends on 95)

The liposomal composition of claim 95, wherein the polyglutamated pralatrexate has 4-6 glutamyl groups in the D-form having gamma carboxyl group linkages.

### Claim 110 (depends on 95)

The liposomal composition of claim 95, wherein the liposome encapsulates between 10-100,000 molecules of polyglutamated pralatrexate having 2-10 glutamyl groups in the D-form.

### Claim 111 (depends on 95)

A pharmaceutical composition comprising the liposomal composition of claim 95.

### Claim 112 (depends on 95)

A method of killing a hyperproliferative cell that comprises contacting a hyperproliferative cell with the liposomal composition of claim 95.

### Claim 113 (depends on 20)

The method of claim 20, wherein the hyperproliferative cell is a cancer cell, a mammalian cell, and/or a human cell.

### Claim 114 (depends on 95)

A method for treating cancer that comprises administering an effective amount of the liposomal composition of claim 95 to a subject having cancer.

### Claim 115 (depends on 95)

A method of preparing a gamma polyglutamated pralatrexate composition comprising the liposomal composition of claim 95, the method comprising: forming a mixture comprising: liposomal components and gamma polyglutamated pralatrexate having 4, 5, 2-10, 4-6, or more than 5, glutamyl groups in the D-form having gamma carboxyl group linkages in solution; homogenizing the mixture to form liposomes in the solution; and processing the mixture to form liposomes containing gamma polyglutamated pralatrexate.