Multi-Valent Eph Receptor Constructs for Glioblastoma Targeting
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Solution Overview
Problem
Current treatments for glioblastoma (GBM) are ineffective due to the lack of specific targets for therapeutic intervention, as most anti-cancer therapeutics target defined intra-cellular compartments, and existing strategies fail to effectively target tumor-initiating cells and tumor neovasculature.
Innovation Solution
Development of constructs comprising ligands that bind EphA2, EphA3, and EphB2, combined with effector molecules such as therapeutic agents or nanoparticles, to target and deliver therapeutic agents to GBM cells, including a fusion protein or covalent conjugate that localizes to specific subcellular compartments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional anti-cancer therapeutics target defined intra-cellular compartments, then treatment specificity is improved, but effectiveness against tumor-initiating cells and tumor neovasculature deteriorates
Solution Approach 1:
The patent applies multi-functionality by designing a single construct that can target multiple receptor sub-populations (EphA2, EphA3, EphB2) on different tumor cell types including tumor-initiating cells and tumor neovasculature. This allows one therapeutic agent to address multiple treatment needs simultaneously, improving overall treatment effectiveness while maintaining specificity through receptor-based targeting.
2Adaptability or versatility
If multiple separate targeting strategies are used to cover different tumor sub-populations, then treatment coverage is improved, but device complexity deteriorates
Solution Approach 1:
The patent merges multiple targeting strategies into a single construct that incorporates ligands for multiple Eph receptors (EphA2, EphA3, EphB2). This consolidation allows the therapeutic agent to simultaneously target different tumor sub-populations including tumor-initiating cells and tumor neovasculature, achieving broad treatment coverage without requiring multiple separate therapies.
Solution Approach 2:
The construct is designed with universal functionality to recognize and bind to multiple receptor types on different tumor cell surfaces, enabling a single agent to address diverse tumor sub-populations that would otherwise require multiple specialized targeting strategies.
3Measurement precision
If EphA3 is specifically activated by ephrin-A5, then signaling specificity is improved, but therapeutic targeting options deteriorate
Solution Approach 1:
The patent overcomes the limitation of EphA3's specific activation requirement by designing a multi-functional construct that targets multiple Eph receptors (EphA2, EphA3, EphB2) simultaneously. This allows the therapeutic agent to activate EphA3 through ephrin-A5 binding while also targeting other Eph receptor sub-populations, thereby maintaining specificity for EphA3 while expanding overall therapeutic targeting options.
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 constructs effectively target and kill GBM cells by simultaneously targeting multiple sub-populations of receptor-overexpressing tumor cells, including tumor-initiating cells and tumor neovasculature, offering a potential for enhanced treatment efficacy and immune response enhancement.
Implementation Method 1
The constructs effectively target and kill GBM cells by simultaneously targeting multiple sub-populations of receptor-overexpressing tumor cells
Data Source
AI summary
Provided herein is a construct comprising, in combination: an EphA3, EphA2 and/or EphB2 binding ligand; and at least one effector molecule. In some embodiments, the at least one effector molecule comprises a therapeutic agent, a nanoparticle, a detectable group, a lipid, or a liposome. In some embodiments, the construct is a fusion protein and/or a covalent conjugate. Further provided is a construct comprising, in combination: a ligand that binds to EphA2, EphA3 and/or EphB2; a ligand that binds to IL-13Rα2; and at least one effector molecule. Also provided are methods of use thereof for treating cancer.