Combination therapy with an anti-hyaluronan agent and therapeutic agent

• US 9,913,822 B2
• Filed: 03/15/2013
• Issued: 03/13/2018
• Est. Priority Date: 04/04/2012
• Status: Active Grant

• Current Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Original Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Inventors: Maneval, Daniel C., Shepard, H. Michael, Thompson, Curtis B.
• Primary Examiner(s): FRONDA, CHRISTIAN L
• Application Number:
  US13/815,804
• Publication Number:
  US 20130302400A1
• Time in Patent Office: 1,824 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/37 Coumarins, e.g. psoralen
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 9/003 Dihydrofolate reductase [DHFR] (1.5.1.3)
• CPC Class Codes: C12N 9/2474 : Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
• CPC Class Codes: C12Y 105/01003 : Dihydrofolate reductase (1.5.1.3)
• CPC Class Codes: C12Y 302/01035 : Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase

Abstract

Provided herein is combination therapy containing an anti-hyaluronan agent, such as a polymer-conjugated hyaluronan-degrading enzyme, and a tumor-targeted taxane, and optionally a further chemotherapeutic agent such as a nucleoside analog. The combination therapy can be used in methods of treating cancers, and in particular solid tumor cancers.

Claims

1. A combination, comprising:

a) a composition comprising a soluble PEGylated PH20 hyaluronidase;

wherein the PH20 hyaluronidase comprises an amino acid sequence that has at least 95% sequence identity to the sequence set forth in SEQ ID NO;

4; and

b) a composition comprising a tumor-targeted taxane that is nab-paclitaxel or nab-docetaxel.

2. The combination of claim 1, wherein:

the compositions are formulated for direct administration;

the concentration of hyaluronidase is sufficient to degrade tumor-associated hyaluronan; and

the concentration of tumor-targeted taxane is sufficient to achieve intratumoral delivery of the taxane.

3. The combination of claim 1, wherein the concentration of tumor-targeted taxane is sufficient to reduce intratumoral nucleoside deaminase protein levels or protein activity compared to the levels or activity of the nucleoside deaminase in the absence of the intratumoral taxane formulation.

4. The combination of claim 1, wherein the hyaluronidase and tumor-targeted taxane are co-formulated for administration in a single composition.

5. The combination of claim 1, further comprising a composition comprising a nucleoside analog, or prodrug thereof, that is a chemotherapeutic agent.

6. The combination of claim 5, wherein:

the composition is formulated for direct administration; and

the concentration of nucleoside analog is sufficient to achieve intratumoral delivery.

7. The combination of claim 5, wherein the nucleoside analog or prodrug thereof is provided separately from the hyaluronidase and tumor-targeted taxane.

8. The combination of claim 5, wherein the nucleoside analog or prodrug thereof is co-formulated with one or both of the hyaluronidase and the tumor-targeted taxane.

9. The combination of claim 1, wherein the compositions are formulated for multiple dosage administration.

10. The combination of claim 1, wherein the compositions are formulated for single dosage administration.

11. The combination of claim 1, wherein:

the hyaluronidase composition contains between or about between 0.5 μ

g to 50 mg hyaluronidase conjugated to a polymer;

or

the hyaluronidase composition contains between or about between 150 Units (U) to 60,000 U hyaluronidase conjugated to a polymer.

12. The combination of claim 11, wherein the volume of the composition containing the hyaluronidase is between or about between 0.5 mL to 100 mL.

13. The combination of claim 1, wherein the hyaluronidase is a PH20 that is a truncated human PH20, a bovine PH20 or an ovine PH20.

14. The combination of claim 1, wherein:

the hyaluronidase is a truncated human PH20;

the hyaluronidase is neutral active and soluble; and

the truncated PH20 comprises an amino acid sequence that contains a contiguous amino acid sequence, including at least amino acids 36-464 of SEQ ID NO;

1 and terminates at a residue selected from 477, 478, 479, 480, 481, 482 or 483, or consists of an amino acid sequence that has at least 98% sequence identity to the polypeptide of SEQ ID NO;

48.

15. The combination of claim 1, wherein the PH20 comprises the amino acid sequence set forth in any of SEQ ID NOS:

4-9, 47, 48, 150-170, 183-189, or an amino acid sequence that has at least 98% sequence identity to an amino acid sequence set forth in any of SEQ ID NOS;

4-9, 47, 48, 150-170, 183-189 and retains hyaluronidase activity.

16. The combination of claim 1, wherein:

the tumor-targeted taxane is formulated as a delivery vehicle selected from among a micelle, nanoparticle, microsphere, liposomes or hydrogel; and

the delivery vehicle is linked directly or indirectly to a tumor targeting moiety.

17. The combination of claim 1, wherein the tumor-targeted taxane composition contains a concentration of tumor-targeted taxane that is between or about between 0.01 mg taxane/mL to 100 mg/mL.

18. The combination of claim 17, wherein the volume of the composition comprising a tumor targeted taxane is between or about between 0.5 mL to 100 mL.

19. The combination of claim 5, wherein the nucleoside analog is a purine or pyrimidine analog or derivatives thereof.

20. The combination of claim 19, wherein the nucleoside analog is selected from among fluoropyrimidine 5-fluorouracil, 5-fluoro-2′

-deoxycytidine, cytarabine, gemcitabine, troxacitabine, decitabine, Azacytidine, pseudoisocytidine, Zebularine, Ancitabine, Fazarabine, 6-azacytidine, capecitabine, N⁴-octadecyl-cytarabine, elaidic acid cytarabine, fludarabine, cladribine, clofarabine, nelarabine, forodesine, and pentostatin, or derivatives thereof.

21. The combination of claim 5, wherein the nucleoside analog composition comprises a concentration of nucleoside analog that is between or about between 1 mg nucleoside analog/ml to 500 mg/ml, 5 mg/mL to 100 mg/ml, 10 mg/mL to 50 mg/mL, 25 mg/mL to 200 mg/mL or 20 mg/mL to 100 mg/mL.

22. The combination of claim 21, wherein the volume of the composition comprising a nucleoside analog is between or about between 0.5 mL to 1000 mL.

23. The combination of claim 1, wherein the composition(s) is (are) formulated for administration orally, intravenously (IV), subcutaneously, intramuscularly, intra-tumorally, intradermally, topically, transdermally, rectally, intrathecally or sub-epidermally.

24. The combination of claim 1, wherein the PEGylation moiety is selected from among polyethylene glycols (PEGs) and methoxypolyethylene glycols (mPEGs).

25. The combination of claim 1, wherein the PEGylation moiety is selected from among methoxypolyethylene glycols (mPEGs).

26. The combination of claim 1, wherein the PEGylation moiety is a PEG, and the PEG is a branched or linear PEG.

27. The combination of claim 1, wherein the PEGylation moiety is produced by reaction with methoxy-poly(ethylene glycol)-succinimidyl butanoate (mPEG-SBA) (5 kDa);

methoxy-poly(ethylene glycol)-succinimidyl butanoate (mPEG-SBA) (20 kDa);

methoxy-poly(ethylene glycol)-succinimidyl butanoate (mPEG-SBA) (30 kDa);

methoxy-poly(ethylene glycol)-succinimidyl α

-methylbutanoate (mPEG-SMB) (20 kDa);

methoxy-poly(ethylene glycol)-succinimidyl α

-methylbutanoate (mPEG-SMB) (30 kDa);

methoxy-poly(ethylene glycol)-butyraldehyde (mPEG-butyraldehyde) (30 kDa), methoxy -poly(ethylene glycol)-succinimidyl propionate (mPEG-SPA) (20 kDa);

methoxy -poly(ethylene glycol)-succinimidyl propionate (mPEG-SPA) (30 kDa);

(methoxy -poly(ethylene glycol)) ₂-N-hydroxysuccinimide ester (mPEG₂-NHS) (10 kDa branched);

methoxy-poly(ethylene glycol)) ₂-N-hydroxysuccinimide ester (mPEG₂-NHS) (20 kDa branched);

(methoxy-poly(ethylene glycol)) ₂-N-hydroxysuccinimide ester (mPEG₂-NHS) 40 kDa branched);

(methoxy-poly(ethylene glycol)) ₂-N-hydroxysuccinimide ester (mPEG₂-NHS) (60 kDa branched);

biotin-poly(ethylene glycol)-N-hydroxysuccinimide ester (biotin-PEG-NHS) (5 kDa biotinylated);

poly(ethylene glycol)-p-nitrophenyl carbonate (PEG-p-nitrophenyl-carbonate) (30 kDa);

or poly(ethylene glycol)-priopionaldehyde (PEG-propionaldehyde) (30 kDa).

28. The combination of claim 1 that is packaged as a kit and optionally includes instructions for use.

29. The combination of claim 5, wherein the soluble PH20 hyaluronidase consists of the amino acid sequence set forth in any of SEQ ID NOS:

4-9, 47, 48, 150-170, 183-189, or an amino acid sequence that exhibits at least 98% sequence identity to an amino acid sequence set forth in SEQ ID NO;

4.

30. The combination of claim 5, wherein the PEGylation moiety is a polyethylene glycol (PEG).

31. The combination of claim 5, wherein the nucleoside analog is gemcitabine or a derivative thereof.

32. The combination of claim 1, wherein the hyaluronidase composition contains between or about between 50 Units hyaluronidase activity (U)/ml to 15,000 U/mL.

33. The combination of claim 5, wherein the nucleoside analog is a substrate for a nucleoside deaminase, and the nucleoside deaminase is adenosine deaminase or cytidine deaminase.

34. The combination of claim 1, comprising:

a) a composition comprising PEGylated soluble PH20 hyaluronidase; and

b) a composition comprising a tumor-targeted taxane that is nab-paclitaxel.

35. The combination of claim 1, wherein:

the soluble PH20 consists of an amino acid sequence that has 98% sequence identity to residues 36-483 of SEQ ID NO;

1; and

the albumin-conjugated taxane is Nab-paclitaxel.