FRα-Binding Antibodies for Blood-Cerebrospinal Fluid Barrier Crossing
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Solution Overview
Problem
The development of central nervous system (CNS) therapeutics is challenging due to the restrictive blood-brain and blood-cerebrospinal fluid barriers, which limit the cerebral bioavailability of pharmaceutical compounds, leading to high dosing requirements and peripheral side effects, and strain production capacities, especially in conditions like Alzheimer's disease and multiple sclerosis.
Innovation Solution
Development of single domain antibodies, particularly VHHs, that bind to the human folate receptor alpha (FRα) at the choroid plexus epithelial cells, enabling receptor-mediated endocytosis and transcytosis to deliver compounds across the blood-cerebrospinal fluid barrier (BCSFB) after a single systemic administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high dosages of pharmaceutical compounds are administered to overcome the blood-cerebrospinal fluid barrier, then the cerebral bioavailability is improved, but peripheral side effects increase and production capacity is strained
Solution Approach 1:
The patent employs the folate receptor alpha (FRα) as an intermediary mediator to transport pharmaceutical compounds across the BCSFB. The FRα binding agent acts as a shuttle that carries the compound through the barrier, enabling targeted delivery to the CNS without requiring high systemic dosages, thereby avoiding peripheral side effects while maintaining production feasibility
Solution Approach 2:
The invention extracts and utilizes the natural folate transport mechanism at the BCSFB by designing compounds that bind to FRα. This extraction of the transport pathway allows selective passage of therapeutics through the barrier, achieving CNS penetration without the need for high dosages that would cause peripheral toxicity
2Quantity of substance
If high dosages of pharmaceutical compounds are administered to overcome the blood-cerebrospinal fluid barrier, then the cerebral bioavailability is improved, but production capacity is strained
Solution Approach 1:
By using FRα as a mediator, the patent enables efficient transport of compounds across the BCSFB at low dosages. This intermediary system maximizes the utilization of each administered molecule, achieving high cerebral bioavailability without straining production capacities
Solution Approach 2:
The invention changes the delivery parameter from high-dose systemic administration to low-dose targeted delivery via FRα binding. This parameter change in dosing strategy achieves equivalent or superior cerebral exposure while dramatically reducing the total production burden
3Ease of operation
If the blood-cerebrospinal fluid barrier is made more permeable to allow compound passage, then drug delivery to CNS is improved, but barrier function and protection are compromised
Solution Approach 1:
The FRα binding agent serves as a legitimate intermediary that exploits the natural, physiologically regulated transport pathway at the BCSFB. This approach maintains barrier integrity by using the body's own transport mechanism rather than disrupting the barrier, thereby achieving drug delivery without compromising protective function
Solution Approach 2:
The invention leverages the BCSFB's own transport system (folate receptor-mediated endocytosis) to deliver drugs. The barrier performs its natural transport function, which is then hijacked for therapeutic delivery, maintaining the barrier's protective role while enabling drug passage through its intended physiological pathway
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 FRα-binding agents facilitate the delivery of therapeutic and diagnostic compounds to the CNS, improving bioavailability and reducing the need for high dosages, thus minimizing side effects and production pressures.
Implementation Method 1
antibodies or antibody fragments including immunoglobulin single variable domain (ISVD) antibodies are disclosed that bind the human folate receptor alpha (hFOLRα) present at the choroid plexus epithelial cells. The invention further relates to the antibodies and the methods herein described for use to increase the delivery of pharmaceutical compounds to the central nervous system via the process of receptor mediated endocytosis and/or transcytosis.
Implementation Method 2
The invention further relates to the antibodies and the methods herein described for use to increase the delivery of pharmaceutical compounds to the central nervous system via the process of receptor mediated endocytosis and/or transcytosis.
Data Source
AI summary
The present invention relates to binding agents specifically binding to the folate transport complex. More specifically, antibodies or antibody fragments including immunoglobulin single variable domain (ISVD) antibodies are disclosed that bind the human folate receptor alpha (hFOLRα) present at the choroid plexus epithelial cells. The invention further relates to the antibodies and the methods herein described for use to increase the delivery of pharmaceutical compounds to the central nervous system via the process of receptor mediated endocytosis and/or transcytosis.