Combination therapy with an anti-hyaluronan agent and therapeutic agent

• US 10,137,104 B2
• Filed: 06/16/2017
• Issued: 11/27/2018
• Est. Priority Date: 04/04/2012
• Status: Expired due to Fees

• 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:
  US15/625,177
• Publication Number:
  US 20170290796A1
• Time in Patent Office: 529 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 cancer therapy effected by administering a polymer-conjugated hyaluronidase, 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 method for treating pancreatic cancer, comprising administering to a subject:

a) a composition comprising a soluble PH20 hyaluronidase, wherein the soluble PH20 hyaluronidase is PEGylated; and

b) a composition comprising a tumor-targeted taxane that is nab-paclitaxel or nab-docetaxel, wherein;

the subject has pancreatic cancer;

the soluble PH20 hyaluronidase comprises a sequence of amino acid residues that has at least 95% sequence identity to the sequence of amino acid residues set forth in SEQ ID NO;

4; and

the composition comprising the PEGylated soluble PH20 hyaluronidase, and the composition comprising the tumor-targeted taxane are administered separately in two compositions or are administered in a single composition.

2. The method of claim 1, wherein the compositions are administered sequentially.

3. The method of claim 1, further comprising administering a composition comprising a nucleoside analog.

4. The method of claim 1, wherein the soluble PH20 hyaluronidase comprises a sequence of amino acids that has at least 98% sequence identity to the sequence set forth in SEQ ID NO:

4.

5. The method of claim 1, wherein:

the hyaluronidase is a truncated PH20; and

the truncated PH20 comprises a sequence of amino acids that contains amino acids 36-464 of SEQ ID NO;

1, or comprises a sequence of amino acids that has at least 95% sequence identity to a sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO;

1 and retains hyaluronidase activity.

6. The method of claim 5, wherein the truncated PH20 comprises a sequence of amino acids set forth in any of SEQ ID NOS:

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

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

7. The method of claim 1, wherein the PEGylation moiety is a polyethylene glycol (PEG), and the PEG is a branched or linear PEG.

8. The method of claim 7, wherein the PEGylation moiety is selected from among methoxypolyethylene glycols (mPEGs).

9. The method of claim 1, wherein:

the hyaluronidase is administered in a dosage range amount of between or about between 0.01 μ

g/kg to 15 μ

g/kg;

or

the hyaluronidase is administered in a dosage range amount of between or about between 10 to 10,000 Units/kg (of the subject).

10. The method 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.

11. The method of claim 1, wherein the composition of b) comprises nab-docetaxel.

12. The method of claim 1, wherein the concentration of the taxane in composition b) is between about 0.01 mg taxane/mL to 100 mg/mL.

13. The method of claim 3, wherein the nucleoside analog is a purine or pyrimidine analog or derivatives thereof.

14. The method of claim 13, 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.

15. The method of claim 3, wherein the nucleoside analog is administered in a dosage range that is between about 100 mg/m2 to 2500 mg/m2 body surface area of the subject.

16. The method of claim 1, wherein the composition(s) are administered orally, intravenously (IV), subcutaneously, intramuscularly, intra-tumorally, intradermally, topically, transdermally, rectally, intrathecally or sub-epidermally.

17. The method of claim 1, wherein the composition(s) is(are) administered intravenously or subcutaneously.

18. The method of claim 1, wherein the hyaluronidase is administered prior to, simultaneously, sequentially or intermittently with the tumor-targeted taxane.

19. The method of claim 18, wherein the hyaluronidase and tumor-targeted taxane are administered simultaneously or near simultaneously.

20. The method of claim 1, wherein:

the frequency of administration of the hyaluronidase is twice weekly, once weekly, once every 14 days, once every 21 days or once every month; and

/or

the frequency of administration of the tumor-targeted taxane is twice weekly, once weekly, once every 14 days, once every 21 days or once every month.

21. The method of claim 3, wherein the hyaluronidase and/or tumor-targeted taxane is administered prior to, simultaneously, sequentially, or intermittently with the nucleoside analog.

22. The method of claim 1, wherein the hyaluronidase and tumor-targeted taxane are administered for a predetermined number of weeks in a cycle of administration.

23. The method of claim 22, wherein the predetermined number of weeks is at least two weeks, at least three weeks or at least four weeks.

24. The method of claim 3, wherein the hyaluronidase and the tumor-targeted taxane are:

administered prior to administration of the nucleoside analog;

administered simultaneously; and

administered at a frequency of administration of twice weekly or once weekly for a predetermined number of weeks.

25. The method of claim 24, wherein the nucleoside analog is administered once weekly for a predetermined number of weeks.

26. The method of claim 24, wherein the hyaluronidase is administered twice weekly and the taxane is administered once weekly.

27. The method of claim 24, wherein the nucleoside analog is administered one week after administration of the hyaluronidase and the tumor-targeted taxane.

28. The method of claim 1, wherein the composition of b) comprises nab-paclitaxel.

29. The method of claim 1, wherein 30% or more of the tumoral area in a tumor biopsy from the subject expresses hyaluronan (HA).

30. The method of claim 29, wherein 50% or more of the tumoral area in the tumor biopsy expresses HA.