Lactonyl-Substituted Antibody-Drug Conjugate Precursor for Stability

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Solution Overview

Problem

Existing antibody-drug conjugates (ADCs) face stability issues in the body due to increased hydrophobicity, leading to aggregation and reduced drug efficacy when the drug-to-antibody ratio (DAR) exceeds optimal levels.

Innovation Solution

A conjugate precursor with lactonyl groups as substituents or protecting groups is used to enhance the hydrophilicity of ADCs, improving their stability in the bloodstream and maintaining potent antitumor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the drug-to-antibody ratio (DAR) is increased to enhance therapeutic effect, then the antitumor efficacy is improved, but the stability of ADC in the body deteriorates due to increased hydrophobicity leading to aggregation

Engineering Contradiction:

Improveantitumor efficacyVSAvoidstability in body

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent introduces lactonyl groups into the conjugate precursor structure to modify the hydrophilicity parameter of the ADC. This chemical parameter change allows the ADC to maintain stability in the body while achieving high DAR (4-8), resolving the contradiction between efficacy and stability by altering the physical-chemical properties of the molecule.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite structure by combining the antibody, linker, cytotoxic drug, and lactonyl groups into an integrated conjugate precursor system. This composite material approach allows the lactonyl groups to contribute hydrophilicity while the other components provide targeting and therapeutic functions, achieving both stability and efficacy simultaneously.

Inventive Principle:

Principle #40Composite materials

2Reliability

If the DAR is increased to improve therapeutic effect, then the drug efficacy is enhanced, but the hydrophobicity increases causing aggregation and reduced stability

Engineering Contradiction:

Improvedrug efficacyVSAvoidhydrophobicity-induced aggregation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of hydrophobicity into a beneficial feature by introducing lactonyl groups that increase hydrophilicity. This transformation allows the ADC to maintain high DAR for enhanced efficacy while the increased hydrophilicity prevents aggregation and improves stability, effectively turning a potential harm into a benefit.

Inventive Principle:

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

Solution Approach 2:

The patent modifies the hydrophilicity parameter of the ADC by incorporating lactonyl groups in the conjugate precursor. This parameter change directly addresses the hydrophobicity-induced aggregation problem, allowing the ADC to achieve high DAR without suffering from aggregation-related stability issues.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If conventional conjugate precursors are used to achieve high DAR, then the therapeutic potency is improved, but the ADC becomes unstable in the bloodstream

Engineering Contradiction:

Improvetherapeutic potencyVSAvoidstability in bloodstream

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the chemical composition parameter of the conjugate precursor by incorporating lactonyl groups. This modification increases the hydrophilicity of the ADC, enabling it to maintain stability in the bloodstream while achieving high DAR and potent therapeutic effect, overcoming the limitations of conventional precursors.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The lactonyl groups act as intermediary elements that mediate between the hydrophobic cytotoxic drug and the hydrophilic antibody environment. These groups serve as a bridge that allows the hydrophobic drug to be incorporated at high DAR while maintaining overall hydrophilicity and stability in the bloodstream.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250170267A1Antibody-drug conjugate precursor and intermediate for synthesis thereof

Publication Date: 2025.05.29 UBE CORPORATION

AI summary

A method for improving the stability of an antibody-drug conjugate in a living body, and a conjugate precursor for producing a stabilized antibody-drug conjugate. An antibody-drug conjugate precursor represented by the following general formula (I) or a salt thereof, a synthetic intermediate thereof or a salt thereof,Z-L-D (I)where Z is a reactive group which can react with a functional group present in an antibody or a modified antibody; D is an antitumor drug residue in which one hydrogen atom or one hydroxy group is removed from any position of an antitumor drug molecule or an analog thereof or a derivative thereof; L is a linker which links Z to D; and at least any one of D and L has one or more lactonyl group(s) at any position(s) as substituent(s) or protecting group(s).