Tomaymycin Derivatives Non-Cleavable Linker Antibody Conjugates
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Solution Overview
Problem
Current cytotoxic agents, such as tomaymycin derivatives, face challenges in targeted delivery to tumor cells, leading to non-specific toxicity and limited potency, with existing linkers either releasing drugs non-specifically or requiring high doses due to impaired binding and rapid clearance.
Innovation Solution
Development of novel tomaymycin derivatives linked to cell binding agents via non-cleavable linkers, ensuring targeted cytotoxic action against tumor cells while minimizing side effects on healthy cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cleavable linkers are used to release drug molecules at the target site, then cytotoxic potency is improved, but non-specific toxicity to bystander cells occurs
Solution Approach 1:
The invention segments the cytotoxic action by using non-cleavable linkers to attach highly potent PBD derivatives directly to the antibody, eliminating the need for drug release. The cytotoxic effect is segmented to occur only within the target cell after internalization, preventing bystander toxicity while maintaining potency through the high intrinsic activity of the PBD derivative.
Solution Approach 2:
The invention changes the parameter of linker cleavability from cleavable to non-cleavable, fundamentally altering the mechanism of action. This parameter change allows the drug-antibody conjugate to maintain stability in circulation and selectively exert cytotoxic effect only after cellular internalization, resolving the contradiction between potency and non-specific toxicity.
2Quantity of substance
If heavily modified antibodies are used to deliver sufficient drug concentration, then cytotoxicity is improved, but binding ability and in vivo stability deteriorate
Solution Approach 1:
The invention changes the parameter of drug potency from moderate to highly potent by selecting PBD derivatives with extremely high intrinsic cytotoxic activity. This parameter change allows the use of fewer drug molecules per antibody (reducing modification density) while still achieving sufficient cytotoxic effect, thereby preserving antibody binding ability and in vivo stability.
3Object-affected harmful factors
If moderate cytotoxicity drugs are used with limited antigen targets, then safety is improved, but therapeutic efficacy deteriorates
Solution Approach 1:
The invention changes the parameter of drug cytotoxicity from moderate to highly potent by using PBD derivatives. This parameter change enables the conjugate to achieve therapeutic efficacy even with limited antigen targets, as the high potency of the PBD derivative compensates for the lower number of target antigens, while the targeted delivery mechanism maintains safety by limiting exposure to healthy cells.
Data Source
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AI summary
The present invention is related to new tomaymycin derivatives having a linking chain between two units of pyrrolo[2,1c][1,4]benzodiazepines, substituted by a non-cleavable linker and their conjugated to cell binding agents, their process of preparation and their therapeutic uses.