CTP-Modified Coagulation Factors for Hemophilia Treatment

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Solution Overview

Problem

Current treatments for hemophilia, particularly Hemophilia B, face challenges in developing long-acting Factor VIIa with prolonged half-life while maintaining biological activity and avoiding immunogenicity, as existing recombinant FVIIa has a short terminal half-life requiring frequent dosing and inducing antibodies.

Innovation Solution

Attaching three chorionic gonadotropin carboxy-terminal peptides (CTPs) to the carboxy terminus of Factor IX and Factor VIIa to extend their biological half-life, improve area under the curve (AUC), and reduce dosing frequency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If recombinant FVIIa is administered to treat hemophilia, then bleeding control is achieved, but the terminal half-life is short (2.5 hours) requiring frequent dosing

Engineering Contradiction:

Improveterminal half-life of FVIIaVSAvoiddosing frequency

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The patent creates a composite protein structure by fusing FVIIa with Fc regions from IgG1, IgG2, or IgG4 antibodies. This composite construction combines the hemostatic function of FVIIa with the long circulatory half-life of antibody Fc regions, achieving extended duration of action without requiring frequent dosing

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The invention merges two separate protein entities (FVIIa and antibody Fc regions) into a single fusion protein. The Fc portion is attached to the C-terminus of FVIIa, creating a unified molecule that leverages the properties of both components to resolve the half-life limitation

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If multiple frequent infusions of rFVIIa are given to achieve adequate homeostasis, then bleeding control is improved, but patient compliance and treatment feasibility decrease

Engineering Contradiction:

Improvehomeostasis controlVSAvoidpatient compliance

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The fusion protein design allows dynamic adjustment of dosing intervals. By extending the half-life through Fc fusion, the treatment regimen can be shifted from frequent short-interval dosing to less frequent long-interval dosing while maintaining reliable hemostatic control, thereby improving ease of operation and patient compliance

Inventive Principle:

Principle #15Dynamics

3Duration of action of moving object

If FVIIa is modified to prolong half-life, then dosing frequency is reduced, but biological activity may be compromised

Engineering Contradiction:

Improvecirculatory half-lifeVSAvoidbiological activity

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The modification is localized to the C-terminus of FVIIa where the Fc region is attached, while the critical functional domains (Gla domain, EGF-like domains, and protease domain) remain unchanged. This localized modification preserves the essential biological activity of FVIIa while extending its circulatory half-life through the Fc portion

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS8759292B2Long-acting coagulation factors and methods of producing same

Publication Date: 2014.06.24 OPKO BIOLOGICS LTD

AI summary

Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions comprising the polypeptides and polynucleotides of the invention and methods of using and producing same are also disclosed.