D-Domain CAR Adapters for Target-Specific Solid Tumor Immunotherapy
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) technology for cancer treatment faces challenges in fully realizing its potential due to limitations in target specificity and efficacy, particularly in solid tumors.
Innovation Solution
Development of D Domain (DD) target binding domains that specifically bind to targets like human CD123, integrated into chimeric antigen receptors (CARs) for enhanced specificity and functionality, along with fusion proteins, nucleic acids, vectors, and host cells for expression and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional CAR technology is used, then general cancer treatment capability is provided, but target specificity and efficacy are limited
Solution Approach 1:
The CAR is divided into distinct functional modules: a D domain binding domain for target recognition, a transmembrane domain for membrane anchoring, and an intracellular signaling domain for immune activation. This segmentation allows each component to be independently optimized for specific functions, thereby improving target specificity while maintaining treatment efficacy through modular design
Solution Approach 2:
The patent employs D domains with specific amino acid sequences (e.g., SEQ ID NO: 8-33, 99 and 100) that bind to CD123 with high affinity. By changing the binding domain parameters to use D domains instead of conventional scFv antibodies, the system achieves enhanced target specificity and efficacy in solid tumors
2Measurement precision
If CARs are engineered for higher target specificity, then binding precision improves, but device complexity increases
Solution Approach 1:
The patent extracts the binding function from conventional antibody-based CARs and replaces it with D domains. This extraction simplifies the overall CAR structure by eliminating the need for complex antibody frameworks while achieving high binding specificity through the D domain's unique CD123 binding capability
Solution Approach 2:
The D domain serves multiple functions simultaneously: it provides target recognition, enables high-affinity binding to CD123, and can be integrated into various CAR configurations (monovalent, multivalent, monospecific, multispecific). This multi-functionality reduces the need for separate components, thereby simplifying the overall CAR structure
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 DD binding domains enhance the specificity and efficacy of CARs, allowing targeted immune responses against cancer cells, including those in solid tumors, with applications in diagnostic and therapeutic settings.
Implementation Method 1
the DD specifically binds a target of interest
Implementation Method 2
the DD binds CD123
Data Source
AI summary
Provided herein are D domain containing polypeptides that specifically bind targets of interest, as are nucleic acids encoding the D domain containing polypeptides, vectors containing the nucleic acids and host cells containing the nucleic acids and vectors. Also provided herein are methods of making and using the D domain containing polypeptides, nucleic acids, vectors and host cells, for example, but not limited to, in diagnostic and therapeutic applications. Also provided herein are multi-functional chimeric antigen receptor (CAR)-based compositions and Adapters and their use in methods of directing immune responses to target cells. In some embodiments, the methods include the use of a CAR expressing cell in combination with an Adapter. The Adapter confers the ability to modulate, alter, and/or direct CAR expressing cell-mediated immune response in vitro and in vivo.