BCMA CAR iNKT Cells With IL-15 for Stronger Binding and Persistence
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Solution Overview
Problem
Existing chimeric antigen receptor (CAR) therapies targeting B-cell maturation antigen (BCMA) exhibit limited binding affinity and persistence, leading to suboptimal cancer cell killing and treatment efficacy.
Innovation Solution
Development of novel BCMA antibodies and chimeric antigen receptors (CARs) for invariant natural killer T (iNKT) cells that enhance binding to BCMA-expressing cells and include IL-15 secretion, promoting enhanced cytotoxicity and persistence in subjects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CAR therapies targeting BCMA are used, then cancer cell killing is achieved, but binding affinity and persistence are limited
Solution Approach 1:
The patent combines multiple functional elements into a single CAR construct: the BCMA-binding antibody domain for target recognition, IL-15 cytokine domain for persistence enhancement, and signaling domains for cytotoxicity activation. This merging of binding, survival, and killing functions into one integrated receptor resolves the contradiction by simultaneously improving both binding affinity and persistence through the unified CAR structure.
Solution Approach 2:
The CAR construct functions as a composite molecular structure integrating different functional domains: antibody variable regions for antigen binding, cytokine domains for immune cell persistence, and signaling domains for activation. This composite architecture allows the single CAR molecule to deliver multiple beneficial effects including enhanced binding affinity and prolonged persistence simultaneously.
2Productivity
If existing CAR therapies targeting BCMA are used, then cancer cell killing is achieved, but treatment efficacy is suboptimal
Solution Approach 1:
The CAR construct includes an IL-15 cytokine domain that enables the T cells to self-support their own persistence and activation without requiring external cytokine administration. The IL-15 expressed by the CAR-T cells themselves creates a self-sustaining system that continuously enhances killing efficacy and maintains therapeutic presence, resolving the contradiction between killing productivity and overall treatment efficacy.
3Reliability
If novel BCMA antibodies and CARs with IL-15 are developed, then binding and killing of BCMA-expressing cells is improved, but device complexity increases
Solution Approach 1:
Rather than adding separate components for binding and persistence, the patent merges the IL-15 cytokine function directly into the CAR structure itself. This consolidation allows the single CAR molecule to provide both target recognition and persistence enhancement, improving killing efficacy while minimizing the increase in overall system complexity compared to using multiple separate therapeutic agents.
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 novel BCMA-targeting iNKT cells demonstrate improved binding and killing of BCMA-expressing cancer cells, along with increased persistence, offering enhanced therapeutic efficacy against cancers such as multiple myeloma.
Implementation Method 1
Chimeric antigen receptors (CAR) proteins and CAR cells directed against BCMA
Implementation Method 2
the iNKT cell kills BCMA expressing cells directly
Implementation Method 3
the iNKT cell comprises a CAR comprising any one of the anti-BCMA antibodies set forth in Table 3
Data Source
AI summary
The present disclosure, at least in part, is based on the discovery of novel BCMA antibodies or antigen binding fragments thereof, and genetically modified cells (e.g., iNKT cells, CAR T cells, etc.) expressing chimeric antigen receptors comprising the anti-BCMA antibody or antigen binding fragment thereof demonstrate improved properties, including increased binding to BCMA, killing of BCMA-expressing cancer cells in vitro and in vivo; and enhanced persistent in a subject receiving the therapy.