B7H3 CAR T Cells Targeting Solid Tumors
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Solution Overview
Problem
Current therapies are inadequate for effectively targeting B7H3, a protein highly overexpressed in various human cancers, which correlates with poor prognosis and clinical outcome.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically binding to B7H3, comprising a single-chain variable fragment (scFv), a transmembrane domain, a spacer, and an intracellular signaling domain, to be expressed in T cells for immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to target B7H3, then treatment is provided, but the therapies are inadequate for effectively targeting B7H3+ tumor cells
Solution Approach 1:
The CAR construct is divided into distinct functional domains: an extracellular antigen-binding domain (scFv) that specifically recognizes B7H3, a transmembrane domain for membrane anchoring, and an intracellular signaling domain for T cell activation. This segmentation allows each component to be optimized independently for its specific function, achieving reliable B7H3 targeting while maintaining T cell effector functions.
Solution Approach 2:
The chimeric antigen receptor acts as an intermediary molecule that bridges the T cell and the B7H3+ tumor cell. The scFv domain binds to B7H3 on the tumor cell surface, while the intracellular signaling domain transmits activation signals to the T cell, thereby mediating the interaction between the immune system and the tumor without requiring endogenous antigen presentation machinery.
2Reliability
If B7H3 is targeted for immunotherapy, then antitumor activity is enhanced, but the complexity of CAR construction increases
Solution Approach 1:
The patent combines multiple functional elements into a single chimeric protein molecule: the antigen-binding scFv, the transmembrane anchoring domain, and the intracellular signaling domain are fused into one continuous polypeptide chain. This merging simplifies the overall therapeutic construct compared to using separate molecules, while still providing the necessary complexity for specific B7H3 recognition and T cell activation.
Solution Approach 2:
The CAR construct functions as a composite molecular structure that integrates components from different sources and functions: the scFv provides antigen-specific binding, the transmembrane domain provides membrane integration, and the intracellular domain provides signaling capability. This composite structure achieves reliable antitumor activity by combining multiple functional properties in a single therapeutic agent.
Data Source
AI summary
Embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to B7H3. Some embodiments relate to cell-based immunotherapy targeting tumors, such as tumors comprising B7H3+ cells.