ALCAM-Binding Moieties for Brain Targeted Cell Delivery
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Solution Overview
Problem
Current therapies face challenges in efficiently delivering therapeutic cells, such as immune cells, across the blood-brain barrier to target pathological sites, particularly in brain tumors and autoimmune diseases, due to the endothelial anergy and disrupted homing molecule expression.
Innovation Solution
The use of an ALCAM-binding moiety, comprising CD6 scavenger receptor cysteine rich domains and stalk sequences, is engineered onto immune cells to enhance their binding to ALCAM on endothelial cells, facilitating targeted delivery across the blood-brain barrier by mimicking the natural ALCAM/CD6 interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapeutic cells are administered, then they can be delivered to general tissues, but they fail to efficiently cross the blood-brain barrier and reach brain pathological sites
Solution Approach 1:
The patent introduces ALCAM-binding moieties as intermediary molecules that mediate the interaction between therapeutic cells and the blood-brain barrier endothelium. These moieties specifically bind to ALCAM on endothelial cells, facilitating cell transmigration across the barrier. This intermediary mechanism overcomes the disrupted natural homing molecule expression and endothelial anergy that prevent conventional cells from reaching brain targets.
Solution Approach 2:
The patent modifies the surface properties of therapeutic cells by engineering them to express ALCAM-binding moieties. This parameter change in cell surface molecular composition enables the cells to recognize and bind to ALCAM on the blood-brain barrier, fundamentally altering their ability to interact with and cross the endothelial barrier compared to conventional unmodified cells.
2Reliability
If ALCAM-binding moieties are engineered onto immune cells, then targeted delivery across the blood-brain barrier is enhanced, but the complexity of cell preparation and engineering increases
Solution Approach 1:
The ALCAM-binding capability is segmented as a separate functional module (the ALCAM-binding moiety) that can be independently engineered and then attached to various therapeutic cell types. This segmentation allows the binding function to be developed and optimized separately from the therapeutic cell itself, simplifying the overall engineering process by modularizing the targeting mechanism.
Solution Approach 2:
The ALCAM-binding moiety serves as a universal targeting component that can be applied to multiple different therapeutic cell types (T cells, NK cells, macrophages, etc.). This universal approach eliminates the need to develop separate targeting mechanisms for each cell type, reducing overall complexity by creating a single versatile solution that works across different therapeutic applications.
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
This approach significantly increases the adhesion and transmigration of therapeutic cells across the endothelial barrier, enabling effective targeting of pathological sites within the brain, including brain tumors and autoimmune disease areas, thereby improving the delivery of therapeutic agents.
Implementation Method 1
Interaction of immune and other cell surface receptor with their cognate adhesion molecules over endothelium is a kick-start for cellular extravasation
Data Source
AI summary
Embodiments of the disclosure concern methods and compositions for delivering therapeutic, diagnostic or interventional moieties, such as complex and simple entities such as biologies, including at least cells, for example. The methods employ targeted delivery by employing at least one ALCAM-binding moiety on the therapeutic, diagnostic or interventional moiety to be delivered. In specific cases, the ALCAM-binding moiety is present on or with the therapeutic moiety in multiple iterations. In certain embodiments, the ALCAM-binding moiety comprises at least one SRCR domain from CD6 and a stalk, such as from CD6, of the secretable or molecular form thereof.