Mesothelin-Targeting Eribulin ADCs for Lower Off-Target Toxicity
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Solution Overview
Problem
Existing cancer therapies face challenges in delivering chemotherapeutics like eribulin in a targeted manner to cancer tissues expressing mesothelin, with limited therapeutic index and significant toxicity to normal tissues, necessitating improved antibodies and antibody-drug conjugates (ADCs) for enhanced tumor targeting and reduced off-target effects.
Innovation Solution
Development of novel antibodies and ADCs, including specific amino acid sequences, that bind to mesothelin and deliver eribulin via cleavable linkers, enabling targeted delivery and internalization into cancer cells, with humanized frameworks to minimize immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapeutics like eribulin are administered to treat cancer, then anti-tumor activity is achieved, but significant toxicity to normal tissues occurs due to limited therapeutic index
Solution Approach 1:
The patent employs mesothelin-targeting antibodies as intermediary carriers that selectively deliver eribulin to cancer cells expressing mesothelin. The antibody acts as a mediator between the cytotoxic drug and the target cell, enabling targeted delivery while sparing normal tissues. This resolves the contradiction by providing tumor-specific targeting to improve therapeutic index.
2Reliability
If antibodies are used to deliver cytotoxic effects to cancer cells, then tumor-specific targeting is achieved, but device complexity increases due to the need for conjugation and linkage chemistry
Solution Approach 1:
The patent segments the therapeutic agent into distinct functional components: the antibody component for targeting, the linker component for connecting, and the eribulin component for cytotoxicity. This segmentation allows each component to be optimized independently while maintaining overall functionality, managing the complexity through modular design.
Solution Approach 2:
The patent utilizes cleavable linkers that undergo parameter changes in response to specific conditions (such as pH or enzymatic cleavage) to release the drug payload. This dynamic parameter change enables controlled drug release while simplifying the conjugation process, as the linker automatically activates under physiological conditions.
3Object-affected harmful factors
If humanized antibodies are used to minimize immunogenicity, then safety is improved, but manufacturing precision requirements increase due to specific amino acid sequence constraints
Solution Approach 1:
The patent applies local quality by humanizing only the critical variable regions (CDRs) of the antibody while maintaining human framework regions. This localized humanization approach minimizes immunogenicity in the most important areas without requiring complete sequence redesign, thereby reducing manufacturing precision requirements compared to fully human antibodies.
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 novel antibodies and ADCs effectively target and kill cancer cells, reducing off-target toxicity and enhancing therapeutic efficacy in mesothelin-expressing cancers, such as mesothelioma, breast, ovarian, and gastric cancers, while maintaining specificity and safety.
Implementation Method 1
anti-mesothelin antibodies and antigen-binding fragments thereof, as well as conjugates such as antibody-drug conjugates (ADCs), e.g., those comprising eribulin
Implementation Method 2
conjugates such as antibody-drug conjugates (ADCs), e.g., those comprising eribulin, and their use in the treatment and diagnosis of cancers
Data Source
AI summary
Antibodies, antigen-binding fragments, and conjugates (e.g., antibody-drug conjugates such as those comprising eribulin) thereof that bind to mesothelin are disclosed. The disclosure further relates to methods and compositions for use in the treatment of cancer by administering the compositions provided herein.