CTP-Modified OXM Peptide Half-Life Extension

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Solution Overview

Problem

Oxyntomodulin (OXM), a dual GLP-1/Glucagon receptor agonist, has a short half-life, requiring repeated daily administrations of supraphysiological doses for pharmacological effect in humans, limiting its prophylactic and therapeutic applications due to its low stability in vivo.

Innovation Solution

A CTP-modified polypeptide is created by attaching chorionic gonadotrophin carboxy terminal peptides (CTP) to the amino or carboxy terminus of OXM, extending its biological half-life and improving its pharmacokinetic profile, including reducing dosing frequency and enhancing glucose tolerance and weight management effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oxyntomodulin is administered repeatedly at supraphysiological doses, then pharmacological effect is achieved, but the treatment complexity and patient burden increase due to frequent dosing

Engineering Contradiction:

Improvepharmacological effectVSAvoiddosing frequency

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies dynamics by modifying the oxyntomodulin peptide structure to change its pharmacokinetic properties. Specifically, CTP moieties are attached to the N-terminus of oxyntomodulin, creating a dynamic modification that extends serum half-life from minutes to hours, enabling transition from frequent dosing to once-daily or less frequent administration while maintaining pharmacological efficacy

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes key pharmacokinetic parameters of oxyntomodulin by attaching CTP moieties. This structural modification alters the peptide's stability, circulation time, and clearance rate, transforming it from a short-acting peptide requiring multiple daily doses to a long-acting analog suitable for once-daily or once-weekly dosing schedules

Inventive Principle:

Principle #35Parameter changes

2Duration of action of moving object

If the half-life of oxyntomodulin is extended through structural modification, then dosing frequency is reduced, but the molecular complexity of the peptide increases

Engineering Contradiction:

Improveserum half-lifeVSAvoidpeptide structure

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

The patent creates a composite peptide structure by combining oxyntomodulin with CTP (chorionic gonadotrophin carboxy terminal peptide) moieties. This composite construction merges the pharmacological activity of oxyntomodulin with the stabilizing and half-life-extending properties of CTP, achieving extended duration of action through a well-defined composite molecular architecture rather than random complexity

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The CTP moiety acts as an intermediary component that mediates between the oxyntomodulin core and the physiological environment. It serves as a bridge that extends circulation time and stability without interfering with the primary pharmacological activity, allowing the active peptide to function effectively over extended periods

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS9522945B2Long-acting oxyntomodulin variants and methods of producing same

Publication Date: 2016.12.20 OPKO BIOLOGICS LTD

AI summary

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.