TfR Apical Domain Constructs for Blood-Brain Barrier Transport
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Solution Overview
Problem
The blood-brain barrier (BBB) restricts the passage of most macromolecules, limiting therapeutic delivery to the brain, and existing methods struggle to effectively target specific receptors across this barrier.
Innovation Solution
A recombinant transferrin receptor (TfR) construct is developed, comprising a monomeric apical domain without a protease-like or helical domain, which retains a conserved epitope and three-dimensional structure, allowing for targeted binding and transport across the BBB, and a modified Fc polypeptide that binds to BBB receptors and the neonatal Fc receptor (FcRn) to enhance brain delivery of therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a full-length transferrin receptor is used for BBB targeting, then receptor binding capability is maintained, but molecular size and complexity increase, reducing delivery efficiency
Solution Approach 1:
The transferrin receptor is divided into functional domains, specifically using only the apical domain (amino acids 1-236) rather than the full-length receptor. This segmentation maintains the essential BBB targeting capability while reducing molecular complexity and size, thereby improving delivery efficiency.
Solution Approach 2:
The invention extracts and utilizes only the critical apical domain of the transferrin receptor that is responsible for BBB targeting, removing the protease-like domain and helical domain that are not essential for this function. This extraction achieves efficient BBB crossing without the burden of unnecessary molecular components.
2Productivity
If macromolecules are designed to cross the BBB, then therapeutic delivery capability is improved, but the blood-brain barrier blocks most macromolecules, limiting passage
Solution Approach 1:
The apical domain of the transferrin receptor serves as an intermediary that mediates the crossing of therapeutic macromolecules through the blood-brain barrier. By conjugating this domain to therapeutic agents, the invention enables these macromolecules to exploit the natural TfR-mediated transport pathway, thereby overcoming the BBB's blocking effect while maintaining therapeutic delivery capability.
3Ease of manufacture
If the apical domain structure is simplified for easier manufacture, then manufacturing ease is improved, but three-dimensional structure conservation may be compromised, affecting epitope recognition
Solution Approach 1:
The invention optimizes the apical domain construct by modifying specific parameters such as adding N-terminal and C-terminal extensions (e.g., Thr-Gly-Ser repeats) to the core apical domain sequence. These parameter changes improve the solubility, stability, and manufacturability of the construct while preserving the critical three-dimensional structure and epitope recognition capability necessary for BBB targeting.
Data Source
AI summary
Provided herein are polypeptides that bind to a blood-brain barrier (BBB) receptor, methods of generating such polypeptides, and methods of using the polypeptides to target a composition to a BBB receptor-expressing cell, e.g., for transport across the BBB. Also provided herein are transferrin receptor (TfR) constructs that comprise a monomeric TfR apical domain or one or more portions of the TfR apical domain which have been circularly permuted relative to the full-length TfR sequence.