Humanized CAR Targeting IGLV3-21R110 BCR in CLL
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Solution Overview
Problem
Current CAR therapies targeting common B-cell antigens like CD19 do not discriminate between healthy and malignant B cells, leading to severe side effects and toxicity in the treatment of chronic lymphocytic leukemia (CLL), particularly in IGLV3-21R110-positive patients, where existing CARs result in off-target killing of healthy B cells.
Innovation Solution
Development of a humanized chimeric antigen receptor (CAR) specifically targeting the IGLV3-21R110-harboring BCR, comprising a humanized light and heavy chain variable regions with defined complementarity-determining regions, which allows selective killing of malignant B-cells without affecting healthy B cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CARs targeting common B-cell antigens like CD19 are used, then leukemia treatment is achieved, but healthy B cells are killed causing severe toxicity
Solution Approach 1:
The CAR is designed to target a specific local feature (IGLV3-21R110 mutation) of the B-cell receptor rather than a general B-cell marker. This allows differentiation between malignant B cells with the specific mutation and healthy B cells without the mutation, enabling selective killing of leukemia cells while sparing normal B cells.
Solution Approach 2:
The invention changes the targeting parameter from common B-cell markers (CD19) to a specific mutation status (IGLV3-21R110). This parameter change enables the CAR to distinguish between malignant and healthy B cells based on the presence or absence of the specific mutation, resolving the contradiction between treatment efficacy and toxicity.
2Reliability
If CARs targeting IGLV3-21R110 are developed, then selective killing of malignant B cells is achieved, but manufacturing complexity increases
Solution Approach 1:
The CAR structure is segmented into distinct functional domains: an antigen-binding domain specific for IGLV3-21R110, a transmembrane domain, and a cytoplasmic signaling domain. This segmentation allows independent optimization of each component, making the complex CAR construct more manageable and manufacturable while maintaining selective killing capability.
Data Source
AI summary
The present invention provides humanized chimeric antigen receptors (CARs) targeting the B-cell receptor (BCR) of CLL cells characterised by R110-mutated immunoglobulin lambda variable 3-21 (IGLV3-21R110).The Invention also provides nucleic acid sequences encoding the forgoing CARs, vectors containing the same, pharmaceutical compositions and kits with instructions for use.