PEGylated Polypeptide Storage Stability via pH Control

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Solution Overview

Problem

PEGylated therapeutic agents undergo dePEGylation during storage, leading to a mixture of PEGylated and dePEGylated molecules, which can result in reduced efficacy and stability, necessitating a method to maintain the PEGylation state.

Innovation Solution

Storing PEGylated polypeptides in a solution buffered to a pH between 2.0 and 6.0, using a maleimide linker to conjugate PEG moieties, and employing specific formulations such as 25 mM succinate with 5% sorbitol or 10 mM sodium acetate with 5% mannitol to inhibit dePEGylation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of stationary object

If PEGylated polypeptides are stored in conventional formulations, then they can be stored for extended periods, but dePEGylation occurs leading to loss of therapeutic efficacy and stability

Engineering Contradiction:

Improvestorage periodVSAvoidPEGylation stability

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent applies parameter changes by adjusting the pH of the storage formulation to a specific range (pH 2.0-6.0, preferably pH 3.0-5.0). This pH adjustment prevents dePEGylation of the maleimide-linked PEG polypeptides during storage, thereby maintaining both the storage duration and the stability of the PEGylation state without compromising therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

2Ease of manufacture

If maleimide linkers are used to conjugate PEG to polypeptides, then PEGylation efficiency is improved, but the linkers are susceptible to cleavage during storage

Engineering Contradiction:

ImprovePEGylation efficiencyVSAvoidmaleimide linker stability

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The patent resolves this contradiction by changing the pH parameter of the storage formulation to pH 2.0-6.0. At this acidic pH range, the maleimide linkers remain stable and resist hydrolysis, while still allowing for efficient PEGylation during manufacturing. This parameter change maintains both manufacturing ease and compositional stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies preliminary action by pre-adjusting the formulation pH to the optimal acidic range before storage begins. This preliminary pH adjustment prevents dePEGylation from occurring during the storage period, ensuring that the maleimide linkers remain intact throughout the storage duration

Inventive Principle:

Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach effectively maintains PEGylation of polypeptides, reducing dePEGylation to less than 5% over several weeks, thereby preserving the stability and efficacy of therapeutic agents.

Implementation Method 1

The maleimide linker may form a thioether bond with a sulfhydryl group on the polypeptide

Methodology Applied

Scientific EffectChemical Bonding: Chemical Bonding

Implementation Method 2

storing the polypeptides in a solution buffered to a pH between 2.0-6.0

Methodology Applied

Scientific EffectBuffering:

Data Source

PatentUS10898538B2Methods for maintaining pegylation of polypeptides

Publication Date: 2021.01.26 BRISTOL MYERS SQUIBB CO

AI summary

Described herein are methods for maintaining PEGylation and inhibiting dePEGylation of polypeptides, such as fibronectin-based scaffold proteins, during storage.