CAR-Modified Macrophages Clearing Protein Aggregates
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Solution Overview
Problem
Current therapeutic approaches for diseases associated with protein misfolding and aggregation, such as neurodegenerative diseases, inflammatory diseases, cardiovascular diseases, and fibrotic diseases, face limitations including inadequate pharmacokinetics, poor tissue penetration, and limited long-term maintenance effects.
Innovation Solution
The use of cells, such as monocytes, macrophages, and dendritic cells, modified to express a chimeric antigen receptor (CAR) with an antigen-binding domain capable of targeting protein aggregates, to disrupt and clear protein aggregates through phagocytosis and other immune mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If therapeutic antibodies are used to target protein aggregates, then specific binding to pathological aggregates is achieved, but tissue penetration and retention are insufficient
Solution Approach 1:
The patent uses antibody-conjugated particles (such as liposomes, micelles, or nanoparticle carriers) as intermediaries to deliver antibodies across the blood-brain barrier and into target tissues. The particle carrier facilitates tissue penetration while the antibody maintains its specific binding capability to protein aggregates, resolving the contradiction between specific binding and tissue penetration.
2Quantity of substance
If high doses of therapeutic antibodies are administered to overcome blood-brain barrier limitations, then brain mAb concentrations increase, but off-site tissue toxicity increases
Solution Approach 1:
The patent employs targeted delivery systems where antibodies are conjugated to particles that specifically accumulate in brain tissue or at sites of protein aggregate deposition. This localized delivery concentrates the antibody effect where needed (high brain mAb concentration) while minimizing exposure to healthy tissues, thereby reducing off-site toxicity even at effective doses.
Solution Approach 2:
Particle carriers serve as intermediaries that protect antibodies from premature clearance and facilitate selective delivery to brain tissue. The particles can be engineered with specific surface properties, size, and targeting ligands to enhance brain uptake while avoiding non-specific accumulation in other organs, thus achieving high brain concentrations with reduced systemic toxicity.
3Reliability
If current antibody-based therapies are used, then aggregate formation is blocked, but long-term maintenance effects are limited
Solution Approach 1:
The patent describes sustained-release formulations and chronic administration regimens that maintain therapeutic antibody levels continuously over long periods. Particle-based delivery systems provide sustained release of antibodies, ensuring continuous blocking of aggregate formation and maintaining therapeutic effects in chronic neurodegenerative conditions.
Solution Approach 2:
The patent employs prophylactic treatment approaches where antibodies are administered before significant aggregate accumulation occurs, or early in disease progression. This preliminary action prevents aggregate formation from establishing, thereby maintaining therapeutic efficacy over the long term with lower doses and reducing the need for intensive long-term maintenance.
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 represents a powerful therapeutic strategy for debilitating diseases by effectively reducing, slowing, or preventing the formation and growth of protein aggregates, thereby improving organ function and reducing morbidity and mortality.
Implementation Method 1
a chimeric antigen receptor (CAR) with an antigen-binding domain capable of targeting protein aggregates
Implementation Method 2
to disrupt and clear protein aggregates through phagocytosis and other immune mechanisms
Data Source
AI summary
The present invention relates to compositions and methods for treating diseases and/or disorders associated with protein aggregates. By expressing a chimeric antigen receptor (CAR) in a monocyte, macrophage or dendritic cell, the modified cell is recruited or applied to the tissue microenvironment where it acts as a potent immune effector by infiltrating the tissue and eliminating, reducing, inhibiting or preventing protein aggregation. Other aspects of this invention include methods and pharmaceutical compositions comprising the CAR modified monocyte, macrophage or dendritic cell for treating a condition, such as a neurodegenerative disease/disorder, an inflammatory disease/disorder, a cardiovascular disease/disorder, a fibrotic disease/disorder and amyloidosis.