Bi-specific CAR T cells targeting CD138 and BCMA for multiple myeloma
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Solution Overview
Problem
Current treatments for multiple myeloma, a type of blood cancer, often lead to resistant relapses, necessitating the development of more effective therapies that can target specific cancer antigens with improved efficacy and safety.
Innovation Solution
The development of bi-specific chimeric antigen receptors (CARs) expressed by T cells, specifically designed to target CD138 and BCMA antigens, incorporating a combination of single chain Fv domains, transmembrane domains, co-stimulatory, and signaling domains to enhance killing activity and include a 'suicide gene' for safety, using lentiviral vectors to modify immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for multiple myeloma are used, then initial response is achieved, but resistant relapses occur and survival is limited
Solution Approach 1:
The CAR T cell receptor is segmented into multiple functional domains: a first scFv domain specific for CD138, a second scFv domain specific for BCMA, a transmembrane domain, and intracellular signaling domains. This segmentation allows the receptor to recognize and bind to multiple different antigens on multiple myeloma cells, enabling the T cells to maintain effectiveness across multiple rounds of targeting and overcoming treatment resistance.
Solution Approach 2:
The bi-specific CAR T cell receptor performs multiple functions by simultaneously targeting two different antigens (CD138 and BCMA) on multiple myeloma cells. This multi-functionality increases the probability of tumor cell recognition and killing, thereby improving treatment efficacy and extending survival duration compared to single-target therapies.
2Productivity
If bi-specific CARs are designed with multiple scFv domains, then killing activity is enhanced, but device complexity increases
Solution Approach 1:
The patent merges two separate single-specificity CAR designs into a single bi-specific CAR structure by connecting the first scFv (CD138-specific) and second scFv (BCMA-specific) domains through a linker. This merging approach consolidates the complexity into a unified receptor structure while maintaining the enhanced killing activity that would otherwise require two separate therapy administrations.
Solution Approach 2:
A linker domain is introduced as an intermediary element between the first scFv and second scFv domains. This linker serves as a structural mediator that allows both antigen-specific binding domains to coexist within a single CAR molecule, enabling the T cell to recognize and target multiple myeloma cells with enhanced killing activity while managing the structural complexity through a defined architectural framework.
3Reliability
If CAR T cells are infused for treatment, then cancer cells are targeted, but safety concerns arise from potential uncontrolled activity
Solution Approach 1:
The patent incorporates a suicide gene (e.g., inducible caspase 9) into the CAR T cell design as a preliminary safety mechanism. This suicide gene remains dormant during normal operation but can be rapidly activated by a specific chemical inducer (e.g., AP20187) to trigger programmed cell death of the infused T cells. This preliminary anti-action prevents uncontrolled or excessive T cell activity from causing harmful effects, while allowing the T cells to maintain full therapeutic effectiveness against cancer cells when the suicide gene is inactive.
Data Source
AI summary
Provided herein are bi-specific chimeric antigen receptors (CARs), such as those specific for CD138 and BCMA. Use of the CARs in immune cells (e.g., T cells), compositions, and methods are also contemplated.