Pegylated OXM variants

• US 10,166,295 B2
• Filed: 05/29/2015
• Issued: 01/01/2019
• Est. Priority Date: 06/02/2011
• Status: Active Grant

• Current Assignee: Opko Biologics Ltd. (Opko Health, Inc.)
• Original Assignee: Opko Biologics Ltd. (Opko Health, Inc.)
• Inventors: Fima, Udi Eyal, Hershkovitz, Oren
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US14/725,883
• Publication Number:
  US 20150258208A1
• Time in Patent Office: 1,313 Days
• Field of Search: None
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

A composition which includes oxyntomodulin and polyethylene glycol polymer (PEG polymer) linked via a reversible linker such as 9-fluorenylmethoxycarbonyl (Fmoc) or sulfo-9-fluorenylmethoxycarbonyl (FMS) is disclosed. Pharmaceutical compositions comprising the reverse pegylated oxyntomodulin and methods of using same are also disclosed.

Claims

1. A method for the preparation of an oxyntomodulin (OXM) conjugate represented by the structure of formula II:

2. The method of claim 1, wherein said MAL-FMS-NHS is prepared by mixing MAL-Fmoc-NHS with trifluoroacetic acid and chlorosulfonic acid.

3. The method of claim 2, wherein MAL-Fmoc-NHS is dissolved in neat trifluoroacetic acid and 6 equivalents of chlorosulfonic acid dissolved in neat trifluoroacetic acid is added to the reaction mixture.

4. The method of claim 1, wherein said protecting group of said Lys¹² and Lys³⁰ is 1-[(4,4-dimethyl-2,6-dioxocyclohex-1-ylidine)ethyl]), (ivDde).

5. The method of claim 1 wherein said reaction with said sulfhydryl PEG polymer (PEG-SH) is conducted under a buffer condition of pH between 6 and 6.5.

6. The method of claim 1, wherein said PEG has a molecular weight in the range of 20,000 Da to 40,000 Da.

7. The method of claim 6, wherein said PEG has a molecular weight with an average molecular weight of 30,000 Da.