Claims for Patent: 8,003,111

Summary for Patent: 8,003,111

Title:	Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo
Abstract:	The present invention concerns methods and compositions for forming PEGylated complexes of defined stoichiometry and structure. In preferred embodiments, the PEGylated complex is formed using dock-and-lock technology, by attaching a therapeutic agent to a DDD sequence and attaching a PEG moiety to an AD sequence and allowing the DDD sequence to bind to the AD sequence in a 2:1 stoichiometry, to form PEGylated complexes with two therapeutic agents and one PEG moiety. In alternative embodiments, the therapeutic agent may be attached to the AD sequence and the PEG to the DDD sequence to form PEGylated complexes with two PEG moieties and one therapeutic agent. In more preferred embodiments, the therapeutic agent may comprise any peptide or protein of physiologic or therapeutic activity, preferably a cytokine, more preferably interferon-.alpha.2b. The PEGylated complexes exhibit a significantly slower rate of clearance when injected into a subject and are of use for treatment of a wide variety of diseases.
Inventor(s):	Chang; Chien-Hsing (Downingtown, PA), Goldenberg; David M. (Mendham, NJ), McBride; William J. (Boonton, NJ), Rossi; Edmund A. (Woodland Park, NJ)
Assignee:	IBC Pharmaceuticals, Inc. (Morris Plains, NJ)
Application Number:	12/731,781
Patent Claims:	1. A PEGylated interferon-.alpha.(IFN-.alpha.) complex comprising: a) a PEG (polyethylene glycol) moiety comprising PEG covalently attached to a first peptide; and b) a fusion protein comprising IFN-.alpha. and a second peptide attached to the C-terminal end of IFN-.alpha.; wherein two copies of second peptide form a dimer that binds to the first peptide to form a PEGylated IFN-.alpha. complex wherein the amino acid sequence of the second peptide is selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2, and the amino acid sequence of the first peptide is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9. 2. The PEGylated IFN-.alpha. complex of claim 1, wherein the IFN-.alpha. is IFN-.alpha.2b. 3. The PEGylated IFN-.alpha. complex of claim 1, wherein the first peptide is selected from the group consisting of: TABLE-US-00018 IMP350 CGQIEYLAKQIVDNAIQQAGC(SS-tbu)-NH.sub.2 (SEQ ID NO: 21), IMP360 CGQIEYLAKQIVDNAIQQAGC(SS-tbu)-G-EDANS (SEQ ID NO: 22), IMP362 PEG.sub.20k-CO-CGQIEYLAKQIVDNAIQQAGCG-NH-(CH.sub.2).sub.2- EDANS (SEQ ID NO: 22), IMP413 mPEG.sub.30K-CGQIEYLAKQIVDNAIQQAGCG-NH-(CH.sub.2).sub.2- EDANS (SEQ ID NO: 22), IMP421 Ac-C-PEG.sub.3-C(SStBu)GQIEYLAKQIVDNAIQQAGCG- NH.sub.2 (SEQ ID NO: 22) and IMP457 Ac-C(mPEG2-Suc 40K)-PEG.sub.3- CGQIEYLAKQIVDNAIQQAGCG-NH.sub.2 (SEQ ID NO: 22). 4. The PEGylated IFN-.alpha. complex of claim 1, wherein the PEGylated IFN-.alpha. complex has a higher anti-viral specific activity than Peginterferon alfa-2b and Peginterferon alfa-2a. 5. The PEGylated IFN-.alpha. complex of claim 1, wherein the PEGylated IFN-.alpha. complex has a higher anti-proliferative effect on cancer cells in vitro than Peginterferon alfa-2b. 6. The PEGylated IFN-.alpha. complex of claim 1, wherein the clearance rate of the PEGylated complex from serum is at least an order of magnitude slower than the clearance rate of unPEGylated IFN-.alpha.. 7. The PEGylated IFN-.alpha. complex of claim 1, wherein the PEGylated IFN-.alpha. complex has greater anti-tumor efficacy in vivo than Peginterferon alfa-2b. 8. A method of treating cancer comprising: a) obtaining a PEGylated complex according to claim 1; and b) administering the PEGylated complex to a subject with cancer. 9. The method of claim 6, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, bone cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal, gastric, head and neck cancer, Hodgkin's lymphoma, lung cancer, medullary thyroid cancer, non-Hodgkin's lymphoma, multiple myeloma, renal cancer, ovarian cancer, pancreatic cancer, glioma, melanoma, liver cancer, prostate cancer, and urinary bladder cancer. 10. A method of delivering a PEGylated interferon-.alpha. (IFN-.alpha.) complex comprising: a) obtaining a PEGylated interferon-.alpha. (IFN-.alpha.) complex according to claim 1; and b) administering the PEGylated interferon-.alpha. (IFN-.alpha.) complex to a subject.

Details for Patent 8,003,111

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	PEGINTRON	peginterferon alfa-2b	Injection	103949	01/19/2001		2025-04-06
Merck Sharp & Dohme Corp.	SYLATRON	peginterferon alfa-2b	For Injection	103949	03/29/2011		2025-04-06
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	10/16/2002		2025-04-06
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	01/07/2004		2025-04-06
Zr Pharma& Gmbh	PEGASYS	peginterferon alfa-2a	Injection	103964	09/29/2011		2025-04-06
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2025-04-06
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	06/13/2008		2025-04-06