Cleavable Linker Topoisomerase Inhibitor Conjugate

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Solution Overview

Problem

Current topoisomerase inhibitors in antibody-drug conjugates face challenges such as decreased cytotoxicity due to steric hindrance, particularly in tumor cells, where the peptidic group is spaced away from the bulky drug moiety, limiting their effectiveness in targeting and releasing the active drug.

Innovation Solution

A topoisomerase inhibitor derivative is conjugated to a linker that attaches to a Ligand Unit, preferably an antibody, via a cleavable connection, allowing for targeted delivery and release of the drug unit directly linked to a peptidic group, enhancing drug loading and specificity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If the peptidic group is spaced away from the bulky drug moiety in current topoisomerase inhibitors, then the conjugate structure is more stable, but the cytotoxicity decreases due to steric hindrance

Engineering Contradiction:

Improveconjugate structure stabilityVSAvoidcytotoxicity

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent inverts the conventional spatial arrangement by placing the peptidic group directly adjacent to the bulky drug moiety rather than spacing it away. This inversion resolves the contradiction by eliminating steric hindrance while maintaining structural stability through the direct linkage configuration.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the spatial parameter (distance) between the peptidic group and drug moiety from a spaced arrangement to a directly linked arrangement. This parameter change eliminates steric hindrance and restores cytotoxicity while the cleavable linker maintains overall conjugate stability.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If a cleavable linker is used to attach the drug unit to the ligand unit, then the drug can be released at the target site, but the drug loading and specificity are limited

Engineering Contradiction:

Improvedrug release capabilityVSAvoiddrug loading

Core Design Contradiction:

Adaptability or versatilityVSQuantity of substance

Solution Approach 1:

The patent employs a nested structure where the drug unit with directly linked peptidic group is integrated into the conjugate framework. This nesting allows the cleavable linker to facilitate drug release while the compact structure maximizes drug loading capacity and target site specificity.

Inventive Principle:

Principle #7Nested doll (Nesting)

3Object-affected harmful factors

If the peptidic group is directly linked to the bulky drug moiety, then the cytotoxicity increases by reducing steric hindrance, but the conjugate synthesis becomes more complex

Engineering Contradiction:

ImprovecytotoxicityVSAvoidconjugate synthesis complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent segments the conjugate into distinct functional units (ligand unit, cleavable linker, drug unit with peptidic group) that can be synthesized separately and then assembled. This segmentation reduces overall synthesis complexity while maintaining the beneficial direct linkage between the peptidic group and drug moiety for high cytotoxicity.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP4176904A1Compounds and conjugates thereof

Publication Date: 2023.05.10 MEDIMMUNE LTD

Figure 1

AI summary

A conjugate comprising the following topoisomerase inhibitor derivative (A*): with a linker for connecting to a Ligand Unit, wherein the linker is attached in a cleavable manner to the amino residue. The Ligand Unit is preferably an antibody. Also provided is A* with the linking unit attached, and intermediates for their synthesis, as well as the released warhead.