Insulin Analog Conjugate with Reduced Receptor Affinity

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Solution Overview

Problem

Current insulin therapies require frequent administration due to insulin's short in vivo half-life, leading to discomfort and inefficiency in managing blood glucose levels for diabetic patients, with existing insulin analogs not effectively extending duration of action.

Innovation Solution

Development of an insulin analog conjugate with specific modifications to the A-chain and B-chain amino acids, linked with a biocompatible material like polyethylene glycol, to enhance the half-life and stability of insulin, reducing receptor-mediated clearance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If insulin is repeatedly administered to maintain therapeutic effect, then blood glucose regulation is improved, but patient compliance and convenience deteriorate due to frequent administration

Engineering Contradiction:

Improveblood glucose regulationVSAvoidpatient compliance

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent modifies the chemical structure of insulin by substituting amino acid residues (e.g., B25Phe→Asp, B25Phe→Glu, A14Tyr→His, A19Tyr→Glu) to create insulin analogs with altered pharmacokinetic properties. These parameter changes in the molecular structure result in extended in vivo half-life and reduced receptor-mediated clearance, allowing less frequent administration while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite insulin formulations by combining insulin analogs with albumin or other carrier proteins to form conjugates. This composite structure protects insulin from degradation, reduces renal clearance, and extends circulation time in the body, thereby maintaining blood glucose regulation with fewer administrations

Inventive Principle:

Principle #40Composite materials

2Duration of action of moving object

If insulin analogs with reduced receptor binding affinity are developed to avoid RMC, then in vivo half-life is improved, but binding affinity to insulin receptors deteriorates

Engineering Contradiction:

Improvein vivo half-lifeVSAvoidbinding affinity to insulin receptors

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent applies local quality modification by making specific, targeted amino acid substitutions at particular positions in the insulin molecule (e.g., B25, B28, A14, A19) rather than uniform modifications throughout the structure. This localized approach allows selective alteration of clearance pathways while preserving critical receptor interaction regions, achieving extended half-life without complete loss of binding affinity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies multiple parameters including amino acid type, substitution position, and conjugation chemistry to optimize the balance between reduced receptor-mediated clearance and maintained therapeutic activity. By adjusting these parameters, the patent achieves analogs with intermediate binding affinity that are sufficient for therapeutic effect while significantly reducing RMC

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11752216B2Insulin analog complex with reduced affinity for insulin receptor and use thereof

Publication Date: 2023.09.12 HANMI PHARM CO LTD

AI summary

The present invention relates to an insulin analog conjugate and use thereof.