CD99-Backbone CAR-T Cells for Solid Tumor Targeting
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Solution Overview
Problem
Current CAR-T cell therapies are limited in their effectiveness against solid tumors due to the immunosuppressive tumor microenvironment and low therapeutic efficiency, as they rely primarily on the CD8 protein backbone for immune synapse formation and stabilization, which is inadequate for sustained tumor targeting.
Innovation Solution
A chimeric antigen receptor (CAR) design incorporating a CD99-derived transmembrane domain and intracellular juxtamembrane domain to enhance immune synapse stabilization and tumor targeting, improving CAR-T cell function and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a conventional CAR backbone (CD8) is used for connecting scFv to signaling domain, then the CAR structure is simple and easy to manufacture, but the immune synapse stabilization is insufficient leading to low therapeutic efficiency against solid tumors
Solution Approach 1:
The invention merges the scFv, transmembrane domain, and intracellular signaling domain into a unified CAR structure where the transmembrane domain is derived from CD99. This integration creates a backbone that inherently provides both structural support and immune synapse stabilization functionality, resolving the contradiction between simplicity and therapeutic efficiency by combining multiple functions into a single integrated component.
Solution Approach 2:
The CAR backbone is constructed as a composite structure combining the extracellular domain of CD99 (for antigen recognition support), the transmembrane domain of CD99 (for membrane anchoring and immune synapse formation), and the intracellular signaling domain (for T cell activation). This composite design achieves superior therapeutic efficiency by leveraging the unique properties of each domain while maintaining overall structural coherence.
2Stability of the object's composition
If the CAR backbone is designed only for physical connection function, then the device complexity is low, but the immune synapse stabilization capability is insufficient
Solution Approach 1:
The CD99-derived transmembrane domain serves multiple functions simultaneously: it anchors the CAR to the cell membrane, facilitates immune synapse formation through its natural adhesion properties, and transmits signaling cues to the intracellular domain. This multi-functionality resolves the contradiction by making the backbone structure itself capable of stabilization without requiring additional separate components.
Solution Approach 2:
The invention changes the fundamental parameter of the transmembrane domain from a simple structural connector to a functionally active component derived from CD99. This parameter change enables the backbone to actively participate in immune synapse stabilization through CD99's natural cell-adhesive properties, thereby achieving enhanced stability without proportionally increasing complexity.
Data Source
AI summary
The present invention relates to a novel chimeric antigen receptor comprising a CD99 region which participates in immune synapse stabilization as a backbone of the chimeric antigen receptor, an immune cell comprising the same, and the uses thereof. CD99-based CAR-T cells are capable of forming very stable immune synapses with tumor cells compared to conventional backbone-based CAR-T cells and can exhibit improved tumor therapeutic efficiency, so they can be useful for immune cell therapy for the treatment of cancer.