Engineered Constant Domains for BBB Transport
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Solution Overview
Problem
The blood-brain barrier (BBB) restricts the passive transfer of therapeutics to the central nervous system (CNS), making it difficult to deliver drugs effectively, as recombinant proteins and antibody therapeutics have limited efficiency in crossing the BBB, and high-dose systemic administration can cause unintended peripheral effects.
Innovation Solution
Development of polypeptides and fusion proteins with engineered constant domains containing heterologous insertions, specifically a heavy chain complementary determining region 3 (CDRH3) or its fragment, which binds to BBB targets, facilitating receptor-mediated transport across the BBB.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If recombinant proteins and antibody therapeutics are administered systemically at high dose to allow for sufficient penetration of the BBB, then therapeutic delivery to the CNS is improved, but unintended peripheral effects occur due to the high dose in the periphery
Solution Approach 1:
The therapeutic protein is segmented into two functional parts: a BBB-targeting domain (CDRH3 or fragment) that mediates crossing of the blood-brain barrier, and a therapeutic payload domain (heterologous polypeptide) that provides the therapeutic effect. This segmentation allows the targeting function to be separated from the therapeutic function, enabling selective delivery to the CNS while minimizing peripheral effects.
Solution Approach 2:
The engineered constant domain acts as an intermediary carrier that facilitates the transport of the therapeutic payload across the BBB. By incorporating a BBB-targeting domain into the constant domain, the intermediary mechanism enables selective penetration of the blood-brain barrier, allowing the therapeutic to reach the CNS without requiring high systemic doses that would cause peripheral toxicity.
2Quantity of substance
If injection of therapeutic directly into the CNS is performed, then therapeutic delivery to the brain is improved, but the procedure is invasive and efficacy is limited by rapid export of CSF containing the therapeutic from the brain to the blood
Solution Approach 1:
The engineered constant domain serves as an intermediary that enables the therapeutic to cross the BBB via receptor-mediated transcytosis. This intermediary mechanism eliminates the need for direct intracranial injection, providing a non-invasive intravenous administration route while maintaining effective brain delivery through the BBB-targeting domain-mediated transport process.
3Adaptability or versatility
If recombinant proteins and antibody therapeutics are administered systemically, then peripheral distribution is achieved, but crossing of the BBB is inefficient
Solution Approach 1:
The therapeutic protein exhibits local quality differentiation through its domain structure: the BBB-targeting domain (CDRH3 or fragment) provides specific affinity for BBB receptors to facilitate crossing, while the heterologous polypeptide domain provides the therapeutic function. This local quality assignment allows efficient BBB penetration without compromising peripheral distribution capabilities.
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
These engineered proteins achieve significant accumulation in the brain, with a 3 to 100-fold increase in vessel-depleted brain fraction, enhancing therapeutic delivery while minimizing peripheral effects.
Implementation Method 1
facilitating receptor-mediated transport across the BBB
Data Source
AI summary
Provided herein are engineered constant domains that have been engineered to comprise a blood brain barrier (BBB)-binding region, such a CDRH3 from an antibody that binds to a blood brain barrier target. Such engineered constant domains can be within a full length antibody or an antigen-binding fragment of an antibody such that the antibody or fragment is capable of binding to both the antigen of the antibody or fragment and the BBB target and is capable of being transported across the BBB.