Affinity-Directed Cleavable Fragment for Site-Specific Antibody Conjugation

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Solution Overview

Problem

Existing antibody-drug conjugates face challenges in achieving site-specific and quantitative modification of small molecule drugs due to complex removal processes of Fc ligands, affecting stability and safety, and random conjugation leads to inconsistent pharmacokinetic and pharmacodynamic data.

Innovation Solution

A cleavable fragment directed by affinity fragment, specifically a thioester structure, is used to prepare a thioester-based acyl transfer reagent for site-specific and quantitative modification of antibodies, allowing for direct and efficient attachment of cytotoxic drugs to antibodies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If Fc ligand guidance method is used for site-specific modification, then modification specificity is improved, but removal process complexity increases

Engineering Contradiction:

Improvemodification specificityVSAvoidremoval process complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention extracts and removes the Fc ligand component from the modification system, replacing it with a thioester-based acyl transfer reagent that achieves site-specific modification without requiring Fc ligand removal steps, thereby simplifying the overall process while maintaining modification specificity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The thioester-based acyl transfer reagent serves as an intermediary that enables direct site-specific modification of antibodies without requiring Fc ligand guidance and subsequent removal, bridging the gap between specificity and process simplicity

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If random conjugation of small molecule drugs is used, then ease of manufacture is improved, but pharmacokinetic and pharmacodynamic consistency deteriorates

Engineering Contradiction:

Improveconjugation easeVSAvoidpharmacokinetic and pharmacodynamic consistency

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The invention applies local quality by directing drug conjugation to specific sites on the antibody molecule through the thioester-based acyl transfer reagent, ensuring that modification occurs at predetermined locations rather than randomly, thereby achieving both ease of manufacture and pharmacokinetic/pharmacodynamic consistency

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The thioester-based acyl transfer reagent is designed with pre-established site-specific binding characteristics, allowing the modification to occur at predetermined locations without requiring complex purification or characterization steps, thus maintaining both ease of manufacture and consistency

Inventive Principle:

Principle #10Preliminary action

3Reliability

If site-specific conjugation in Fc domain is implemented, then antibody stability and efficacy are improved, but modification process complexity increases

Engineering Contradiction:

Improveantibody stability and efficacyVSAvoidmodification process complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention extracts the complex Fc ligand guidance mechanism and replaces it with a simplified thioester-based acyl transfer reagent that directly achieves site-specific modification in the Fc domain, maintaining antibody stability and efficacy while reducing process complexity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the chemical parameters of the modification process by using thioester-based acyl transfer reagents with specific reactivity characteristics, enabling site-specific conjugation in the Fc domain under optimized conditions that simplify the overall process while maintaining reliability

Inventive Principle:

Principle #35Parameter changes

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 enables stable and safe site-specific drug conjugation, ensuring consistent quality and uniform pharmacokinetic data, enhancing the efficacy and stability of antibody-drug conjugates.

Implementation Method 1

the carbonyl group contained in the functional fragment directly covalently forms an amide bond with the lysine residue

Methodology Applied

Scientific EffectNucleophilic attack: Chemical Bonding

Implementation Method 2

AT is an affinity moiety for target protein (TP)

Methodology Applied

Scientific EffectReversible covalent bonding: Chemical Bonding

Data Source

PatentUS20250345444A1Cleavable fragment directed by affinity fragment, design and synthesis thereof, and use thereof in preparation of site-directed drug conjugate

Publication Date: 2025.11.13 SHANGHAI INSTITUTE OF MATERIA MEDICA CHINESE ACADEMY OF SCIENCES

AI summary

A cleavable fragment directed by an affinity fragment, the design and the synthesis thereof, and the use thereof in the preparation of a site-directed drug conjugate are provided. Specifically, a conjugate with a ligand affinity directing group is as represented by formula I: AT-CL-R (I). AT is an affinity moiety for a target protein (TP); CL is a cleavable fragment which has a self-cleaving reactivity; and R is a group to be modified to the target protein.