HGF Binding Agent Stabilization with Nonpolar Amino Acids

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Solution Overview

Problem

Current compositions for hepatocyte growth factor (HGF) do not effectively stabilize specific binding agents, such as antibodies, over time, particularly at elevated pH levels, leading to instability and potential loss of biological activity.

Innovation Solution

A composition comprising a specific binding agent to HGF, a stabilizing agent (nonpolar amino acids like alanine, leucine, or methionine), and a buffering agent, maintained at a pH above 5.4, which includes additional pharmaceutical agents and cryoprotectants to enhance stability and prevent discoloration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If conventional compositions are used for HGF binding agents, then the composition can be formulated, but the binding agent becomes unstable over time especially at elevated pH levels

Engineering Contradiction:

Improvestability of specific binding agentVSAvoidbiological activity retention

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent applies parameter changes by optimizing the pH range to above 5.4 and incorporating specific nonpolar amino acids (alanine, leucine, methionine) at defined concentrations to stabilize the binding agent. These parameter adjustments prevent aggregation and denaturation while maintaining biological activity over extended storage periods.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The composition uses a composite formulation combining the specific binding agent with multiple stabilizing components including nonpolar amino acids, buffering agents, and optionally cryoprotectants. This composite approach creates a synergistic system that provides comprehensive stabilization against various degradation mechanisms including aggregation, denaturation, and freeze-thaw damage.

Inventive Principle:

Principle #40Composite materials

2Reliability

If the composition is stored at elevated pH levels, then the binding activity can be maintained, but aggregation and denaturation occur

Engineering Contradiction:

Improvebinding activityVSAvoidaggregation and denaturation

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Nonpolar amino acids serve as intermediary stabilizing agents that mediate between the elevated pH conditions and the binding agent. These amino acids interact with the binding agent to prevent aggregation and denaturation while allowing the pH to remain in the optimal range for binding activity, effectively acting as a protective buffer.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The composition incorporates stabilizing agents beforehand to cushion against potential damage from elevated pH storage conditions. This preventive approach ensures that when the composition is stored at pH above 5.4, the binding agent is already protected from aggregation and denaturation mechanisms.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Adaptability or versatility

If the composition undergoes freeze-thaw cycles, then storage flexibility is improved, but discoloration and activity loss occur

Engineering Contradiction:

Improvestorage flexibilityVSAvoidbiological activity and appearance

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

Cryoprotectants are incorporated into the composition beforehand to cushion against the damaging effects of freeze-thaw cycles. These agents prevent ice crystal formation and associated mechanical damage to the binding agent, thereby maintaining both biological activity and appearance stability during frozen storage and thawing operations.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Solution Approach 2:

The composition formulation is optimized with specific stabilizing agents that enable the system to withstand temperature fluctuations. The presence of nonpolar amino acids and optional cryoprotectants changes the physical parameters of the solution to prevent denaturation and discoloration during freeze-thaw transitions.

Inventive Principle:

Principle #35Parameter changes

4Ease of operation

If the composition is exposed to light, then handling and administration is facilitated, but discoloration occurs

Engineering Contradiction:

Improvehandling convenienceVSAvoidcolor stability

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

Methionine in the composition acts as a sacrificial antioxidant that converts the harmful effect of light exposure into a beneficial outcome. By preferentially oxidizing itself, methionine protects the binding agent from light-induced oxidation and discoloration, allowing the composition to be handled and stored under normal lighting conditions without degradation.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS7951368B2Compositions of specific binding agents to hepatocyte growth factor

Publication Date: 2011.05.31 AMGEN INC

AI summary

Compositions comprising nonpolar amino acids and specific binding agents to hepatocyte growth factor (HGF) are provided. Methods of making and using such compositions are also provided.