Claims for Patent: 9,920,311

Summary for Patent: 9,920,311

Title:	PEGylated L-asparaginase
Abstract:	Disclosed is a conjugate of a protein having substantial L-asparagine aminohydrolase activity and polyethylene glycol. In particular, the polyethylene glycol has a molecular weight less than or equal to about 5000 Da and the protein is an L-asparaginase from Erwinia. The conjugate of the invention has shown superior properties such as maintenance of a high level of in vitro activity and an unexpected increase in half-life in vivo. Also disclosed are methods of producing the conjugate and use of the conjugate in therapy. In particular, a method is disclosed for use of the conjugate in the treatment of cancer, particularly Acute Lymphoblastic Leukemia (ALL). More specifically, a method is disclosed for use of the conjugate as a second line therapy for patients who have developed hypersensitivity or have had a disease relapse after treatment with other L-asparaginase preparations.
Inventor(s):	Abribat; Thierry (Sainte Foy les Lyon, FR)
Assignee:	Jazz Pharmaceuticals II SAS (Lyons, FR)
Application Number:	14/819,305
Patent Claims:	1. A conjugate comprising an L-asparaginase from Erwinia chrysanthemi having at least 90% sequence identity to the amino acid of SEQ ID NO:1 and conjugated to at least one polyethylene glycol (PEG) molecule, wherein the at least one PEG has a molecular weight less than 5000, 4000, 3000, or 2500 Da and the conjugate has at least fifty times more in vivo L-asparaginase activity compared to an Erwinia chrysanthemi L-asparaginase not conjugated to PEG. 2. The conjugate of claim 1, wherein said L-asparaginase has at least 95% to 99% sequence identity to the amino acid of SEQ ID NO: 1. 3. The conjugate of claim 1, wherein said L-asparaginase comprises the amino acid of SEQ ID NO: 1. 4. The conjugate of claim 1, wherein the PEG is covalently linked to one or more amino groups of said L-asparaginase. 5. The conjugate of claim 4, wherein the PEG molecules are covalently linked to at least from about 40% to about 100% of the accessible amino groups of said L-asparaginase. 6. The conjugate of claim 1 having the formula: Asp-[NH--CO--(CH.sub.2)x-CO--NH-PEG]n wherein Asp is the L-asparaginase, NH is one or more of the NH groups of the lysine residues and/or the N-terminus in the Asp, PEG is a polyethylene glycol moiety, n is a number that represents at least 40% to 100% of the accessible amino groups in the Asp, and x is an integer ranging from 1 to 8. 7. The conjugate of claim 1, wherein said PEG is monomethoxy-polyethylene glycol. 8. The conjugate of claim 1, wherein said conjugate has at least sixty, seventy, eighty, ninety or one-hundred times more in vivo L-asparaginase activity compared to an Erwinia chrysanthemi L-asparaginase not conjugated to PEG. 9. The conjugate of claim 1, wherein the conjugate has increased residual enzymatic activity in vivo when compared to Erwinia chrysanthemi L-asparaginase conjugated to at least one PEG molecule with a molecular weight of 10,000 Da. 10. The conjugate of claim 1, wherein the L-asparaginase does not cross-react with antibodies which react with Escherichia coli L-asparaginase. 11. The conjugate of claim 1 comprising an L-asparaginase from Erwinia chrysanthemi consisting of the amino acid of SEQ ID NO: 1 and the conjugate has reduced immunogenicity when administered to a human subject hypersensitive to Escherichia coli L-asparaginase. 12. The conjugate of claim 1, wherein the conjugate has an in vitro L-asparaginase activity of at least 60%, 70%, 80%, or 87% of an L-asparaginase not conjugated to PEG. 13. The conjugate of claim 1, wherein said PEG has a molecular weight of less than 5000 Da. 14. The conjugate of claim 1, wherein the PEG molecules are covalently linked to at least 60%, 70%, 80%, 90% or 100% of the accessible amino groups of said L-asparaginase.

Details for Patent 9,920,311

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	January 10, 1978		2035-08-05
Jazz Pharmaceuticals, Inc.	ERWINAZE	asparaginase erwinia chrysanthemi	For Injection	125359	November 18, 2011		2035-08-05