Engineered CB1 Binding Proteins With Restricted Brain Penetration
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Solution Overview
Problem
Existing CB1 inverse agonists and antagonists face challenges in safely targeting peripheral CB1 receptors without significant penetration through the blood-brain barrier, leading to adverse CNS effects.
Innovation Solution
Development of engineered CB1 binding proteins, such as antibodies and antigen-binding fragments, designed to specifically bind to CB1 receptors with modified complementarity determining regions (CDRs) to restrict brain penetration and modulate CB1 signaling peripherally.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule CB1 inverse agonists/antagonists are used to target peripheral CB1 receptors, then therapeutic effects on obesity and metabolic disorders are achieved, but significant penetration through the blood-brain barrier causes adverse CNS side effects
Solution Approach 1:
The patent uses peripherally restricted antibodies as intermediary agents that bind to CB1 receptors exclusively in peripheral tissues. These engineered antibodies serve as mediators between the therapeutic goal (CB1 modulation) and the safety requirement (no CNS penetration), achieving peripheral CB1 antagonism without crossing the blood-brain barrier, thereby eliminating CNS side effects while maintaining therapeutic efficacy
Solution Approach 2:
The patent applies local quality by engineering antibodies with modified complementarity determining regions (CDRs) that confer peripheral tissue specificity. The antibodies are designed to recognize and bind CB1 receptors in peripheral tissues (liver, adipose, muscle) with high affinity while lacking the ability to cross the blood-brain barrier, creating a spatially differentiated therapeutic action that concentrates effects where needed and avoids harmful areas
2Ease of operation
If CB1 inverse agonists are designed to cross the blood-brain barrier for central action, then CNS effects are achieved, but serious psychiatric problems occur
Solution Approach 1:
The patent inverts the conventional approach by designing antibodies that explicitly cannot cross the blood-brain barrier. Instead of trying to prevent CNS penetration as a limitation, the invention makes peripheral restriction the defining feature through engineered CDR regions, turning what was a constraint into the core mechanism for achieving safety while maintaining therapeutic utility
3Reliability
If peripherally selective CB1 antagonists are developed, then CNS side effects are reduced, but development is still in early stages or limited to non-human research
Solution Approach 1:
The patent applies parameter changes by systematically modifying the complementarity determining regions (CDRs) of antibodies to optimize peripheral tissue binding affinity and specificity. Through iterative engineering of CDR sequences and structures, the invention achieves nanomolar affinity for peripheral CB1 receptors while maintaining the size and physicochemical properties that prevent blood-brain barrier penetration, accelerating translational readiness
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 engineered CB1 binding proteins effectively inhibit or modulate CB1 signaling in peripheral tissues, reducing CNS side effects and providing a safer therapeutic approach for conditions like obesity, diabetes, and liver diseases.
Implementation Method 1
engineered CB1 binding proteins, such as antibodies and antigen-binding fragments, designed to specifically bind to CB1 receptors with modified complementarity determining regions (CDRs)
Data Source
AI summary
The present disclosure provides isolated, engineered, non-naturally occurring CB1 binding proteins, including anti-CB1 antibodies or antigen-binding fragment thereof. The CB1 binding proteins find utility in the treatment and diagnosis of CB1 mediated conditions, diseases and disorders.