Targeted liposomal gemcitabine and methods thereof

Patent metadata

Field	Value
Publication number	US-2021154140-A1
Application number	US-202117165534-A
Country	US
Kind code	A1
Filing date	Feb 2, 2021
Priority date	May 4, 2016
Publication date	May 27, 2021
Grant date	—

Abstract

This disclosure relates to a targeted PEGylated liposomal gemcitabine (PLG) composition comprising a PEGylated liposome encapsulating one or more agents comprising gemcitabine and a targeting moiety; pharmaceutical composition and methods comprising PLG or producing PLG; and manufacturing equipment for performing the methods.

First claim

What is claimed is:

1 . A targeted PEGylated liposomal gemcitabine (PLG) composition, comprising:
a PEGylated liposome encapsulating one or more agents, wherein the one or more agents comprises gemcitabine; and one or more targeting moiety comprising an amino acid chain, the amino acid chain comprising a plurality of amino acids, at least one of the one or more targeting moiety having a specific affinity for at least one type of folate receptor, the one or more targeting moiety attached to one or both of a PEG and an exterior of the liposome.

2 . The targeted PLG composition of claim 1 , wherein the amino acid chain comprises a peptide or a protein.

3 . The targeted PLG composition of claim 2 , wherein the protein comprises an antibody, a fragment of an antibody or a component of an antibody.

4 . The targeted PLG composition of claim 1 , wherein the PEGylated liposome further comprising one or more of an immunostimulatory agent, a detectable marker and a maleimide disposed on at least one of the PEG and the exterior of the liposome.

5 . The targeted PLG composition of claim 1 , wherein the PEGylated liposome is an anionic liposome or a neutral liposome.

6 . The targeted PLG composition of claim 1 , wherein the specific affinity has an equilibrium dissociation constant (Kd) between 0.5×10 −10 to 10×10 −6 moles [0.05 nanoMole to 10 μMole] for at least one type of folate receptor.

7 . The targeted PLG composition of claim 1 , wherein at least one of the targeting moiety has the specific affinity for one or more selected from the group consisting of folate receptor alpha, folate receptor beta and folate receptor delta.

8 . The targeted PLG composition of claim 7 , wherein at least one of the targeting moiety has the specific affinity for folate receptor alpha and folate receptor beta.

9 . The targeted PLG composition of claim 1 , wherein at least one of the targeting moiety has the specific affinity for an epitope on a tumor cell surface antigen that is present on a tumor cell but absent or inaccessible on a non-tumor cell.

10 . The targeted PLG composition of claim 9 , wherein the epitope is part of the ligand binding site of a folate receptor.

11 . The targeted PLG composition of claim 9 , wherein the epitope is not on the ligand binding site of a folate receptor.

12 . The targeted PLG composition of claim 9 , wherein the tumor cell surface antigen comprises one or more selected from the group consisting of: folate receptor alpha, folate receptor beta, and folate receptor delta.

13 . The targeted PLG composition of claim 1 , wherein the one or more targeting moiety comprises one or more selected from the group consisting of: an antibody, a humanized antibody, an antigen binding fragment of an antibody, a single chain antibody, a single-domain antibody, a mono-specific antibody, a bi-specific antibody, a synthetic antibody, a pegylated antibody, and a multimeric antibody.

14 . The targeted PLG composition of claim 1 , wherein the targeted PLG composition has an encapsulation efficiency of at least 10% or an encapsulation capacity of at least 5%.

15 . The targeted PLG composition of claim 1 , wherein the PEGylated liposome has a diameter in the range selected from the group consisting of:
20 nm to 200 nm; and 80 nm to 130 nm.

16 . The targeted PLG composition of claim 1 , wherein the liposomes do not contain encapsulated cytidine deaminase.

17 . The targeted PLG composition of claim 16 wherein the cytidine deaminase is one or more of the enzymes that converts gemcitabine and other nucleotide analogues into inactive forms in patient plasma, produced in tumor microenvironment by TAMs, and/or associated with hypoxic tumor microenvironment.

18 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 1 , wherein the one or more agents comprises one or more selected from the group consisting of: platinum; platinum derivative; taxane; taxane derivative; camptothecin; and camptothecin derivative.

19 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 , wherein the platinum derivative is one or more selected from the group consisting of cisplatin, carboplatin and oxaliplatin.

20 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 which, when administered to a patient, results in a molar ratio of gemcitabine to platinum or gemcitabine to platinum derivative in the tumor micro-environment in a range of about 16:1 to about 1:64, or about 1:2.

21 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 , wherein the taxane derivative is one or more selected from the group consisting of paclitaxel, taxotere and cabazitaxel.

22 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 which, when administered to a patient, results in a molar ratio of gemcitabine to taxane or gemcitabine to taxane derivative in the tumor micro-environment in a range of about 16:1 to about 1:64, or about 1:2.

23 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 , wherein the camptothecin derivative is one or more selected from the group consisting of irinotecan, SN-38, and CPT-11.

24 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 which, when administered to a patient, results in a molar ratio of gemcitabine to camptothecin or gemcitabine to camptothecin derivative in the tumor micro-environment in a range of about 16:1 to about 1:64, or about 1:2.

25 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 18 , wherein the PLG, when administered, results in a molar ratio of [gemcitabine] to [platinum or platinum derivative] to [taxane or taxane derivative] to [camptothecin or camptothecin derivative] in the tumor micro-environment in a range of about 16:1:1:1 to about 1:64:64:64 or with a ratio of about 1:2:2:2.

26 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 1 wherein said PEGylated liposome further comprising one or more selected from the group consisting of a hapten and an antigen.

27 . The targeted PEGylated liposomal gemcitabine (PLG) composition of claim 26 wherein the hapten is one or more selected from the group consisting of fluorescein and Beta 1, 6-glucan.

28 . A pharmaceutical composition comprising the targeted PEGylated liposomal gemcitabine (PLG) composition of claim 1 .

29 . A method of delivering gemcitabine to a tumor expressing a folate receptor on its surface, the method comprising the step of:
administering the targeted PLG composition of claim 1 in an amount to deliver a therapeutically effective dose of the gemcitabine to the tumor.

30 . The method of claim 29 , wherein the tumor is in a subject and the administering is selected from the group consisting of: infusion; injection; parenteral administration; topical administration; intraperitoneal injection; direct intratumor injection; intra-arterial injection; intravenous injection; subcutaneous injection; intramuscular injection; transcutaneous delivery; and intranasal delivery.

31 . The method of claim 29 , wherein the subject is a human.

32 . The method of claim 29 , wherein the subject is a non-human mammal.

33 . A method for treating cancer in a

Assignees

• L E A F Holdings Group Llc

Inventors

• Niyikiza Clet
• Moyo Victor
• Xu Zhenghong
• KHALIFA Kaniz

Classifications

• A61K31/7068 Primary

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/569

  Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody® · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title