Claims for Patent: 10,016,491

Summary for Patent: 10,016,491

Title:	Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
Abstract:	The invention relates to the discovery of novel soluble neutral active Hyaluronidase Glycoproteins (sHASEGPs), methods of manufacture, and their use to facilitate administration of other molecules or to alleviate glycosaminoglycan associated pathologies. Minimally active polypeptide domains of the soluble, neutral active sHASEGP domains are described that include asparagine-linked sugar moieties required for a functional neutral active hyaluronidase domain. Included are modified amino-terminal leader peptides that enhance secretion of sHASEGP. The invention further comprises sialated and pegylated form of a recombinant sHASEGP to enhance stability and serum pharmacokinetics over naturally occurring slaughterhouse enzymes. Further described are suitable formulations of a substantially purified recombinant sHASEGP glycoprotein derived from a eukaryotic cell that generate the proper glycosylation required for its optimal activity.
Inventor(s):	Bookbinder; Louis H. (San Diego, CA), Kundu; Anirban (Georgetown, KY), Frost; Gregory I. (Palm Beach, FL)
Assignee:	Halozyme, Inc. (San Diego, CA)
Application Number:	14/936,290
Patent Claims:	1. A pharmaceutical composition, comprising: a) a soluble neutral active human hyaluronidase glycoprotein (sHASEGP), wherein: the hyaluronidase glycoprotein is active at neutral pH and contains at least one sugar moiety that is covalently attached to an asparagine (N) residue of the hyaluronidase polypeptide; the hyaluronidase polypeptide does not comprise the complete sequence of amino acids set forth in SEQ ID NO:1; and the hyaluronidase polypeptide consists of: (i) a contiguous sequence of amino acid residues contained within SEQ ID NO:1 that includes at least amino acids 36-464 of SEQ ID NO:1, wherein the polypeptide is truncated within the C-terminus of SEQ ID NO:1 at a C-terminal amino acid residue selected from among 477, 478, 479, 480, 481, 482, 483 and 494 of SEQ ID NO:1; or (ii) a sequence of amino acid residues that has at least 95% amino acid sequence identity with a sequence of amino acids set forth in (i); and b) immune globulins (IG). 2. The pharmaceutical composition of claim 1, wherein the hyaluronidase glycoprotein has a C-terminal amino acid residue selected from among 477, 478, 479, 480, 481, 482 and 483 of SEQ ID NO:1. 3. The pharmaceutical composition of claim 1, wherein: (i) the hyaluronidase glycoprotein consists of the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1; or (ii) the hyaluronidase glycoprotein contains amino acid substitutions in the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1, whereby the amino acid-substituted hyaluronidase glycoprotein consists of a sequence of amino acids that has at least 95% amino acid sequence identity with the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1. 4. The pharmaceutical composition of claim 3, wherein the hyaluronidase glycoprotein contains amino acid substitutions in the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1, whereby the amino acid-substituted hyaluronidase glycoprotein consists of a sequence of amino acids that has at least 97% amino acid sequence identity with the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1. 5. The pharmaceutical composition of claim 1 that comprises a hyaluronidase glycoprotein that has a C-terminal amino acid residue selected from among 479, 480, 481 and 482. 6. The pharmaceutical composition of claim 1, wherein the hyaluronidase polypeptide consists of a sequence of amino acids that has at least 98% sequence identity with residues 36-483 of SEQ ID NO:1. 7. The pharmaceutical composition of claim 1, wherein the hyaluronidase glycoprotein is expressed and secreted from mammalian cells. 8. The pharmaceutical composition of claim 7, wherein the mammalian cells are Chinese Hamster Ovary (CHO) cells. 9. The pharmaceutical composition of claim 1, wherein the hyaluronidase glycoprotein is modified with a polymer. 10. The pharmaceutical composition of claim 9, wherein the polymer is PEG or dextran. 11. The pharmaceutical composition of claim 1 that is formulated for subcutaneous administration. 12. The pharmaceutical composition of claim 1 that is formulated for intravenous administration. 13. The composition of claim 1, wherein the immune globulin is selected from among cytomegalovirus immune globulin, hepatitis B immune globulin, immune globulin intramuscular, immune globulin intravenous, rabies immune globulin, respiratory syncytial virus immune globulin, immune globulins (IG), tetanus immune globulin and varicella-zoster immune globulin. 14. The composition of claim 1, wherein the immune globulin comprises human immune globulins (human IG). 15. A combination, comprising: a) a first composition comprising a soluble neutral active human hyaluronidase glycoprotein (sHASEGP), wherein: the hyaluronidase glycoprotein is active at neutral pH and contains at least one sugar moiety that is covalently attached to an asparagine (N) residue of the hyaluronidase polypeptide; the hyaluronidase polypeptide does not comprise the complete sequence of amino acids set forth in SEQ ID NO:1; and the hyaluronidase polypeptide consists of: (i) a contiguous sequence of amino acid residues contained within SEQ ID NO:1 that includes at least amino acids 36-464 of SEQ ID NO:1, wherein the polypeptide is truncated within the C-terminus of SEQ ID NO:1 at a C-terminal amino acid residue selected from among 477, 478, 479, 480, 481, 482, 483 and 494 of SEQ ID NO:1; or (ii) a sequence of amino acid residues that has at least 95% amino acid sequence identity with a sequence of amino acids set forth in (i); and b) a second composition that is immune globulins (IG). 16. The combination of claim 15, wherein the hyaluronidase glycoprotein has a C-terminal amino acid residue selected from among 477, 478, 479, 480, 481, 482 and 483 of SEQ ID NO:1. 17. The combination of claim 15, wherein: (i) the hyaluronidase glycoprotein consists of the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1; or (ii) the hyaluronidase glycoprotein contains amino acid substitutions in the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1, whereby the amino acid-substituted hyaluronidase glycoprotein consists of a sequence of amino acids that has at least 95% amino acid sequence identity with the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1. 18. The combination of claim 15, wherein the hyaluronidase glycoprotein has a C-terminal amino acid residue selected from among 477, 478, 479, 480, 481, 482 and 483 of SEQ ID NO:1. 19. The combination of claim 15, wherein the hyaluronidase glycoprotein contains amino acid substitutions in the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1, whereby the amino acid-substituted hyaluronidase glycoprotein consists of a sequence of amino acids that has at least 95% amino acid sequence identity with the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1. 20. The combination of claim 15, wherein the hyaluronidase glycoprotein contains amino acid substitutions in the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1, whereby the amino acid-substituted hyaluronidase glycoprotein consists of a sequence of amino acids that has at least 97% amino acid sequence identity with the sequence of amino acids set forth as amino acids 36-477, 36-478, 36-479, 36-480, 36-481, 36-482, or 36-483 of SEQ ID NO:1. 21. The combination of claim 15, wherein the hyaluronidase polypeptide consists of a sequence of amino acids that has at least 98% sequence identity with residues 36-483 of SEQ ID NO:1. 22. The combination of claim 15, wherein the hyaluronidase glycoprotein is expressed and secreted from mammalian cells. 23. The combination of claim 22, wherein the mammalian cells are Chinese Hamster Ovary (CHO) cells. 24. The combination of claim 15, wherein the hyaluronidase glycoprotein is modified with a polymer. 25. The combination of claim 24, wherein the polymer is PEG or dextran. 26. The combination of claim 15, wherein the first and second compositions are formulated for subcutaneous administration. 27. The combination of claim 15, wherein the immune globulin is selected from among cytomegalovirus immune globulin, hepatitis B immune globulin, immune globulin intramuscular, immune globulin intravenous, rabies immune globulin, respiratory syncytial virus immune globulin, immune globulin (IG), tetanus immune globulin and varicella-zoster immune globulin. 28. The combination of claim 15 wherein the immune globulin comprises human immune globulins (human IG).

Details for Patent 10,016,491

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2023-03-05
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	12/02/2004		2023-03-05
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	10/26/2004		2023-03-05
Akorn, Inc.	HYDASE	hyaluronidase	Injection	021716	10/25/2005		2023-03-05
Grifols Therapeutics Llc	BAYGAM, GAMASTAN S/D	immune globulin (human)	Injection	101134	01/11/1944		2023-03-05
Grifols Therapeutics Llc	GAMMAKED (KENDRION), GAMUNEX-C	immune globulin injection (human) 10% caprylate/chromatography purified	Injection	125046	08/27/2003		2023-03-05