PEGylated Four Helical Bundle Polypeptides for Extended Half-Life

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Solution Overview

Problem

Current therapies for growth hormone (GH), interferon (IFN), and granulocyte Colony-Stimulating Factor (G-CSF) face challenges such as short in vivo half-life, requiring frequent administration, and issues with bioavailability and stability, leading to undesirable side effects and limited therapeutic efficacy.

Innovation Solution

Incorporation of non-naturally encoded amino acids into these polypeptides, specifically within the four helical bundle (4HB) structure, to enhance stability, bioavailability, and therapeutic half-life by linking them to water-soluble polymers like polyethylene glycol (PEG), thereby modulating their pharmacokinetic properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If growth hormone polypeptides are administered therapeutically, then therapeutic effects are achieved, but the in vivo half-life is short requiring frequent administration

Engineering Contradiction:

Improvein vivo half-lifeVSAvoidadministration frequency

Core Design Contradiction:

Duration of action of moving objectVSProductivity

Solution Approach 1:

The patent applies composite materials by combining growth hormone polypeptides with polyethylene glycol (PEG) polymers to create PEGylated fusion proteins. This composite structure increases the hydrodynamic radius and decreases renal clearance of the therapeutic protein, thereby extending its in vivo half-life from hours to days, which directly reduces the frequency of administration required to maintain therapeutic efficacy.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent changes physical parameters of the growth hormone by attaching PEG chains with varying molecular weights (e.g., 2kDa, 5kDa, 10kDa, 20kDa) to the polypeptide. This parameter change in molecular size and hydrophilicity modifies the pharmacokinetic properties, specifically increasing serum half-life and altering biodistribution, which allows for less frequent dosing intervals.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If growth hormone polypeptides are administered therapeutically, then therapeutic effects are achieved, but bioavailability is limited leading to reduced efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies the physicochemical parameters of growth hormone by PEGylation, which increases water solubility and stability of the polypeptide. The attached PEG chains create a hydrophilic corona that prevents aggregation and proteolytic degradation, thereby improving bioavailability and ensuring more reliable therapeutic efficacy through consistent drug delivery.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If growth hormone polypeptides are administered at high doses to improve efficacy, then therapeutic effects are enhanced, but side effects increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the pharmacokinetic parameters of growth hormone through PEGylation, extending half-life and improving bioavailability. This allows achieving the same therapeutic efficacy at lower doses because the PEGylated protein remains in circulation longer and is more efficiently delivered to target tissues, thereby reducing the need for high dosing that causes side effects.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS8906676B2Modified human four helical bundle polypeptides and their uses

Publication Date: 2014.12.09 AMBRX INC

AI summary

Modified human four helical bundle (4HB) polypeptides and uses thereof are provided.