GPRC5D-Targeting CARs for Multiple Myeloma
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Solution Overview
Problem
Current adoptive T cell therapies for multiple myeloma face challenges due to limited expression of target antigens like CD19 and high expression of other antigens in normal tissues, leading to 'off-tumor, on-target' toxicity, necessitating novel strategies for CARs that target antigens highly expressed in myeloma cells with minimal normal tissue expression.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically targeting G-protein coupled receptor family C group 5 member D (GPRC5D) with high affinity, using extracellular antigen-binding domains such as scFv or Fab, to minimize toxicity and maximize tumor eradication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CARs target common myeloma markers (CD138, CD38, CD56), then tumor recognition is achieved, but off-tumor toxicity occurs due to expression on normal cells
Solution Approach 1:
The patent extracts the target antigen GPRC5D from the list of common myeloma markers (CD138, CD38, CD56) that cause off-tumor toxicity. By identifying and using GPRC5D as the target, the CAR therapy achieves tumor recognition without the harmful off-tumor effects associated with conventional markers, as GPRC5D is selectively expressed on myeloma cells and not on normal tissues.
Solution Approach 2:
The patent changes the target antigen parameter from conventional markers to GPRC5D, which has different expression characteristics. This parameter change results in a CAR that maintains high tumor recognition capability while eliminating off-tumor toxicity, as GPRC5D is uniquely expressed on myeloma cells compared to normal tissues.
2Strength
If CARs use high affinity binding domains (scFv, Fab), then binding strength to GPRC5D is improved, but manufacturing complexity increases
Solution Approach 1:
The patent segments the CAR into functional domains: extracellular antigen-binding domain (scFv or Fab), transmembrane domain, and intracellular signaling domain. This segmentation allows optimization of the binding affinity component (scFv/Fab) independently while maintaining overall CAR functionality, achieving high affinity without excessive overall complexity.
Solution Approach 2:
The patent changes the binding domain parameter to use scFv or Fab formats, which provide high affinity binding to GPRC5D. This parameter change in the binding domain structure achieves strong tumor cell binding while the modular nature of these formats keeps the manufacturing process manageable compared to more complex receptor designs.
Data Source
AI summary
The presently disclosed subject matter provides for methods and compositions for treating multiple myeloma. It relates to chimeric antigen receptors (CARs) that specifically target a G-protein coupled receptor (e.g., a G-protein coupled receptor family C group 5 member D (GPRC5D)), and immunoresponsive cells comprising such CARs. The presently disclosed CARs targeting a G-protein coupled receptor (e.g., GPRC5D) have enhanced immune-activating properties, including anti-tumor activity.