Targeted liposomal gemcitabine and methods thereof

Patent metadata

Field	Value
Publication number	US-12115256-B2
Application number	US-202117165534-A
Country	US
Kind code	B2
Filing date	Feb 2, 2021
Priority date	May 4, 2016
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

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 method of delivering gemcitabine to a tumor expressing a folate receptor on its surface, the method comprising the step of: administering a pharmaceutical composition comprising a targeted PEGylated liposomal gemcitabine (PLG) in an amount to deliver a therapeutically effective dose of the gemcitabine to the tumor, wherein the targeted PLG comprises: a unilamellar anionic PEGylated liposome encapsulating one or more agents, wherein the PEGylated liposome has a diameter in the range 80 nm to 130 nm wherein the one or more agents comprises gemcitabine and Beta 1, 6-glucan; wherein the PLG comprises one or more targeting moiety comprising an antibody, a fragment of an antibody or a component of an antibody having a specific affinity for at least one type of folate receptor, the one or more targeting moiety conjugated to one or more maleimide moieties attached to-one or both of a PEG and an exterior of the liposome.

2. The method of claim 1 , wherein the tumor is in a patient 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.

3. The method of claim 2 , wherein the patient is a human.

4. The method of claim 2 , wherein the patient is a non-human mammal.

5. The method of claim 1 , wherein the PEGylated liposome further comprises one or more of an immunostimulatory agent, a detectable marker and a maleimide moiety disposed on at least one of the PEG and the exterior of the liposome.

6. The method of claim 1 , wherein the targeted PLG comprises a targeting moiety having an equilibrium dissociation constant (Kd) between 0.5×10 −10 to 10×10 −6 moles for at least one type of folate receptor.

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

8. The method of claim 1 , wherein the targeted PLG comprises one or more targeting moiety 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.

9. The method of claim 1 , wherein the PLG does not contain encapsulated cytidine deaminase.

10. The method of claim 9 , 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 tumor associated macrophages (TAMs), and/or associated with hypoxic tumor microenvironment.

11. The method of claim 1 , wherein the targeted PLG further comprises one or more agents selected from the group consisting of: platinum; platinum derivative; taxane; taxane derivative; camptothecin; and a camptothecin derivative.

12. A method for treating cancer in a patient comprising administering to the patient an effective amount of a pharmaceutical composition comprising a targeted PEGylated liposome encapsulating gemcitabine and Beta 1, 6-glucan, wherein the exterior of the liposome comprises one or more targeting moiety comprising an antibody, a fragment of an antibody or a component of an antibody having a specific affinity for at least one type of folate receptor (PLG).

13. The method of claim 12 wherein the cancer is a tumor.

14. The method of claim 13 wherein the tumor expresses a folate receptor.

15. The method of claim 13 wherein the method inhibits or reduces tumor cell proliferation.

16. The method of claim 12 wherein the cancer is one or more selected from the group consisting of: pancreatic cancer; breast cancer; ovarian cancer; bladder cancer; lung cancer; prostate cancer; head cancer; neck cancer; gastric cancer; gastrointestinal cancer; colon cancer; esophageal cancer; cervical cancer; kidney cancer; biliary duct cancer; gallbladder; hematologic malignancy; leukemia; lymphoma; and mesothelioma.

17. The method of claim 12 , wherein the patient is a human.

18. The method of claim 12 , wherein the patient is a non-human mammal.

19. The method of claim 12 , wherein the targeted PEGylated liposome PbG comprises a targeting moiety having an equilibrium dissociation constant (Kd) between 0.5×10 −1 to 10×10 −6 moles for at least one type of folate receptor.

20. The method of claim 12 , wherein the targeted PEGylated liposome comprises at least one targeting moiety having specific affinity for one or more selected from the group consisting of folate receptor alpha, folate receptor beta and folate receptor delta.

21. The method of claim 12 , wherein the targeted PEGylated liposome comprises one or more targeting moiety 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.

22. The method of claim 12 , wherein the targeted PEGylated liposome does not contain encapsulated cytidine deaminase.

23. The method of claim 22 , 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 tumor associated macrophages (TAMs), and/or associated with hypoxic tumor microenvironment.

24. The method of claim 12 , wherein the targeted PEGylated liposome further comprises one or more agents selected from the group consisting of: platinum; platinum derivative; taxane; taxane derivative; camptothecin; and a camptothecin derivative.

Assignees

• L E A F Holdings Group Llc

Inventors

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

Classifications

• C07K2317/92

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

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/569

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

• C07K2317/31

  multispecific · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title