Non-cleavable Linker Maytansinoid Conjugates for Targeted Delivery

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Solution Overview

Problem

Existing targeted delivery methods for maytansinoids, such as those using cleavable linkers, often result in reduced cytotoxic potency and increased side effects due to inefficient linkage with cell-binding agents, limiting their effectiveness in treating diseases like cancer.

Innovation Solution

The use of non-cleavable linkers to conjugate maytansinoids with cell-binding agents, such as antibodies, maintains cytotoxic potency while reducing plasma clearance and toxicity, allowing for targeted delivery with minimal side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cleavable linkers are used to conjugate maytansinoids with cell-binding agents, then the conjugates can be designed to release the cytotoxic agent inside target cells, but the cytotoxic potency is reduced and plasma clearance increases

Engineering Contradiction:

Improvetargeted delivery efficiencyVSAvoidcytotoxic potency and plasma clearance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical parameter of the linker from cleavable to non-cleavable, fundamentally altering its stability profile. This parameter change transforms the linker into a permanent connector that prevents premature drug release in plasma while maintaining sufficient cellular uptake and intracellular activity, thereby resolving the contradiction between targeted delivery efficiency and cytotoxic potency preservation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Instead of designing the linker to be cleavable (conventional approach), the patent inverts the logic by using a non-cleavable linker. This inversion challenges the assumption that cleavability is necessary for targeted delivery, demonstrating that stable linkers can achieve equivalent or superior antitumor activity while reducing plasma clearance and improving overall therapeutic efficacy

Inventive Principle:

Principle #13The other way round (Inversion)

2Object-affected harmful factors

If non-cleavable linkers are used to conjugate maytansinoids with cell-binding agents, then cytotoxic potency is maintained and plasma clearance is reduced, but the stability of the conjugate must be ensured

Engineering Contradiction:

Improvecytotoxic potency and plasma clearanceVSAvoidconjugate stability

Core Design Contradiction:

Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent modifies the stability parameter of the linker by selecting non-cleavable chemical structures (e.g., stable amide or ether bonds) that resist hydrolysis and enzymatic degradation in plasma. This parameter change ensures the conjugate remains intact during circulation, preventing premature drug release while maintaining sufficient stability for cellular internalization and intracellular cytotoxic activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs simple, stable chemical linkers that do not require complex cleavable structures. These straightforward linkers provide sufficient stability for the application, avoiding the need for elaborate cleavage mechanisms while maintaining effective targeted delivery and cytotoxic potency

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Productivity

If maytansinoids are targeted to specific cell populations, then therapeutic efficacy is improved, but side effects and toxicity must be minimized

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects and toxicity

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the linker stability parameter to non-cleavable, which alters the pharmacokinetic profile of the conjugate. This parameter change reduces plasma clearance and extends circulation time, allowing for more efficient target cell accumulation and internalization. The result is improved therapeutic efficacy at lower doses, thereby reducing systemic toxicity and side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The non-cleavable linker enables the conjugate to self-deliver the cytotoxic agent directly to target cells through receptor-mediated endocytosis. The stable linkage ensures the drug remains attached during circulation and is released only upon cellular internalization, allowing the system to self-regulate drug delivery without requiring external cleavage triggers, thus improving therapeutic index

Inventive Principle:

Principle #25Self-service

Data Source

PatentUS10844135B2Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates and methods of making said

Publication Date: 2020.11.24 IMMUNOGEN INC

AI summary

The present invention discloses a method for targeting maytansinoids to a selected cell population, the method comprising contacting a cell population or tissue suspected of containing the selected cell population with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non-cleavable linker and the cell-binding agent binds to cells of the selected cell population.