CTP-Fused Factor VIIa for Extended Half-Life and Reduced Immunogenicity

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Solution Overview

Problem

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

Innovation Solution

Attaching three to five chorionic gonadotrophin carboxy-terminal peptides (CTPs) to the carboxy terminus of Factor VII (FVII) polypeptides to extend biological half-life, improve dosing frequency, and reduce clearance rates, thereby enhancing the coagulation factor's potency and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If recombinant FVIIa is administered to treat hemophilia, then bleeding episodes can be controlled, but the half-life is short requiring frequent dosing

Engineering Contradiction:

Improvehalf-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 the CTP peptide from chorionic gonadotrophin. This composite construct (FVIIa-CTP) combines the hemostatic function of FVIIa with the extended circulation properties of CTP, achieving prolonged half-life without requiring frequent dosing

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The CTP peptide acts as an intermediary that mediates between the FVIIa molecule and the immune system. It serves as a carrier that extends circulation time while potentially reducing immunogenicity, allowing FVIIa to remain in circulation longer without being rapidly cleared

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If recombinant FVIIa is administered frequently, then hemostatic activity is maintained, but patient compliance and quality of life decrease

Engineering Contradiction:

Improvehemostatic activity maintenanceVSAvoidpatient compliance

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

By creating the FVIIa-CTP composite, the patent reduces dosing frequency from multiple times daily to potentially once weekly or less, significantly improving patient compliance while maintaining reliable hemostatic protection through the extended half-life of the modified protein

Inventive Principle:

Principle #40Composite materials

3Reliability

If conventional FVIIa is used, then treatment is effective, but inhibitory antibodies are induced reducing long-term efficacy

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidinhibitory antibodies

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The CTP peptide serves as an intermediary carrier that may shield the immunogenic epitopes of FVIIa. By having CTP as the prominent surface feature rather than FVIIa, the immune system may recognize and respond to CTP instead, potentially reducing the formation of inhibitory antibodies against the therapeutic FVIIa portion

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11066658B2Long-acting coagulation factors and methods of producing same

Publication Date: 2021.07.20 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.