Para-amino-benzyl Linkers for ADC Aggregation Reduction

Solution Overview

Problem

Current antibody-drug conjugates (ADCs) face issues with aggregation and poor solubility due to hydrophobic nature of cytotoxic agents and limitations of self-immolative linkers like PAB, which can lead to reduced drug loading and pharmacological activity.

Innovation Solution

Development of novel para-amino-benzyl linker compounds that combine a para-amino-benzyl unit with a peptide unit, optimizing the structure to reduce aggregation and enhance stability and drug loading in ADCs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If self-immolative linkers like PAB are used to attach cytotoxic drugs to antibodies, then targeted delivery is achieved, but aggregation and poor solubility occur due to the hydrophobic nature of cytotoxic agents

Engineering Contradiction:

Improvetargeted deliveryVSAvoidaggregation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The linker is divided into distinct functional segments: a hydrophilic portion (containing polar groups like hydroxyl, carboxyl, or amide groups) and a self-immolative portion (PAB or PABC unit). This segmentation allows the hydrophilic segment to counteract aggregation while the self-immolative segment enables targeted drug release at the tumor site.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The linker combines chemically distinct components with complementary properties: the hydrophilic portion improves solubility and reduces aggregation, while the self-immolative portion provides enzymatic cleavability and drug release functionality. This composite structure resolves the contradiction between targeted delivery and aggregation prevention.

Inventive Principle:

Principle #40Composite materials

2Reliability

If self-immolative linkers like PAB are used to attach cytotoxic drugs to antibodies, then targeted delivery is achieved, but drug loading is reduced due to solubility limitations

Engineering Contradiction:

Improvetargeted deliveryVSAvoiddrug loading

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The linker is divided into distinct functional segments: a hydrophilic portion (containing polar groups like hydroxyl, carboxyl, or amide groups) and a self-immolative portion (PAB or PABC unit). This segmentation allows the hydrophilic segment to counteract aggregation while the self-immolative segment enables targeted drug release at the tumor site.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention modifies the chemical parameters of the linker by introducing hydrophilic groups (hydroxyl, carboxyl, amide) that change the overall polarity and solubility characteristics of the conjugate, thereby increasing the achievable drug loading without compromising targeted delivery.

Inventive Principle:

Principle #35Parameter changes

3Power

If hydrophobic cytotoxic agents are linked to antibodies, then potent therapy is achieved, but aggregation occurs leading to reduced pharmacological activity

Engineering Contradiction:

Improvetherapeutic potencyVSAvoidaggregation

Core Design Contradiction:

PowerVSObject-generated harmful factors

Solution Approach 1:

The hydrophilic portion of the linker acts as an intermediary between the hydrophobic cytotoxic drug and the antibody, reducing direct hydrophobic interactions that lead to aggregation while maintaining the drug's potent therapeutic activity through the self-immolative release mechanism.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The linker combines chemically distinct components with complementary properties: the hydrophilic portion improves solubility and reduces aggregation, while the self-immolative portion provides enzymatic cleavability and drug release functionality. This composite structure resolves the contradiction between targeted delivery and aggregation prevention.

Inventive Principle:

Principle #40Composite materials

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

The new linker compounds result in ADCs with low aggregation levels, improved stability, and desirable drug loading, maintaining pharmacological activity.

Implementation Method 1

said drug is enzymatically cleaved from the conjugate at a particular cell or tissue type targeted by said antibody

Methodology Applied

Scientific EffectEnzymatic cleavage: Enzyme

Implementation Method 2

The aromatic amine becomes electron-donating and initiates an electronic cascade that leads to the expulsion of the leaving group, which releases the free drug after elimination of carbon dioxide

Methodology Applied

Scientific EffectElectronic cascade:

Implementation Method 3

The amide bond linking the carboxy terminus of a peptide unit and the para-aminobenzyl of PABC or PAB may be a substrate and cleavable by certain proteases

Methodology Applied

Scientific EffectProtease cleavage: Enzyme

Data Source

PatentEP4153242B1Para-amino-benzyl linkers, process for their preparation and their use in conjugates

Publication Date: 2024.05.15 LES LAB SERVIER SA

Figure 1~2
Figure 3

AI summary

The present invention relates to para-amino-benzyl linker compounds useful for linking drug moieties to antibodies, to linker-drug compounds in which said para-amino-benzyl linker compounds are covalently linked to drug moieties, and to antibody-drug conjugates in which said para-amino-benzyl linker compounds are covalently linked to drug wherein said drug is enzymatically cleaved from the conjugate at a particular cell or tissue type targeted by said antibody.