Long-acting oxyntomodulin variants and methods of producing same
Inventors
Fima, Udi Eyal Eyal • HERSHKOVITZ, Oren
Assignees
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Publication Number
US-9522945-B2
Publication Date
2016-12-20
Expiration Date
Abstract
This invention is directed to a chorionic gonadotrophin carboxy terminal peptide (CTP) modified dual GLP-1/glucagon receptor agonist, and methods of producing and using the same. In one embodiment, the present invention provides a CTP-modified polypeptide comprising a dual GLP-1/glucagon receptor agonist and at least one chorionic gonadotrophin carboxy terminal peptide (CTP) attached to the amino terminus or carboxy terminus of the agonist.
Core Innovation
The invention provides a CTP-modified polypeptide comprising a dual GLP-1/glucagon receptor agonist, wherein one to five chorionic gonadotropin carboxy terminal peptides (CTP) are attached to the amino terminus or carboxy terminus of the agonist. The CTP is from the beta-subunit of human chorionic gonadotropin and comprises amino acid positions 1-10 of SEQ ID NO:3.
The described engineered constructs include dual GLP-1/glucagon receptor agonist polypeptides designated as OXM and modified by addition of CTP in different copy numbers from one up to five and in different attachment-site arrangements on the agonist termini. The document further describes variants in which at least one CTP is glycosylated or truncated, and variants that lack a signal peptide.
The document reports transient expression and purification of the engineered OXM-CTP fusion proteins and comparative in vivo pharmacokinetics in rats. The addition of CTP prolongs the OXM half-life and increases exposure, and functional in vivo studies include an IPGTT in mice showing improved glucose tolerance for several OXM-CTP variants, and a food intake study showing reduced food intake for longer than native OXM.
Claims Coverage
The document contains three independent claims. The main inventive features are a CTP-modified dual GLP-1/glucagon receptor agonist polypeptide with defined CTP sequence origin and positional attachment options, a pharmaceutical composition comprising the CTP-modified polypeptide, and a method of producing the CTP-modified polypeptide by attaching the CTPs to the agonist termini.
CTP-modified dual GLP-1/glucagon receptor agonist polypeptide with 1 to 5 CTPs
A CTP-modified polypeptide comprising a dual GLP-1/glucagon receptor agonist and one to five chorionic gonadotropin carboxy terminal peptides (CTP) attached to the amino terminus or carboxy terminus of said agonist.
CTP identity from beta-subunit of human chorionic gonadotropin (amino acid positions 1-10)
The CTP is from the beta-subunit of human chorionic gonadotropin and comprises amino acid positions 1-10 of SEQ ID NO:3.
Pharmaceutical composition comprising the CTP-modified polypeptide
A pharmaceutical composition comprising the CTP-modified polypeptide.
Producing a CTP-modified dual GLP-1/glucagon agonist polypeptide by CTP attachment
A method of producing a CTP-modified polypeptide comprising a dual GLP-1/glucagon receptor agonist and one to five chorionic gonadotropin carboxy terminal peptide (CTP) attached to said agonist, the method comprising the step of attaching one to five chorionic gonadotropin carboxy terminal peptides to the amino terminus or carboxy terminus of said agonist.
Overall, the claim coverage focuses on attaching one to five CTP peptides, derived from the beta-subunit of human chorionic gonadotropin and comprising amino acid positions 1-10 of SEQ ID NO:3, to the amino terminus or carboxy terminus of a dual GLP-1/glucagon receptor agonist, and on pharmaceutical compositions comprising the defined CTP-modified polypeptide and methods of producing it.
Stated Advantages
Extended serum pharmacokinetics (improved half-life and increased AUC) relative to native OXM.
Reduced dosing frequency associated with long-acting pharmacology.
Preserved glucose tolerance activity while prolonging food intake inhibition.
Prolonged OXM half-life when CTP is added.
Increased exposure for CTP-modified OXM.
Improved glucose tolerance in IPGTT for several OXM-CTP variants.
Reduced food intake for longer than native OXM, with durable inhibition for OXM-CTPx5.
Documented Applications
Pharmaceutical compositions comprising the CTP-modified polypeptides.
In vivo pharmacokinetics evaluation of OXM-CTP variants, including half-life and exposure measurements in rats.
Glucose tolerance testing by IPGTT in mice to assess improved glucose tolerance for OXM-CTP variants.
A food intake study to assess inhibition of food intake by OXM-CTP variants compared with native OXM.
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