Humanized BCMA-CAR-T Cells for Specific Myeloma Targeting
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Solution Overview
Problem
Current CAR-T cell therapies targeting BCMA in multiple myeloma have limitations in specificity and efficacy, as they may not effectively distinguish between BCMA-positive and BCMA-negative cells, leading to off-target effects and reduced antitumor activity.
Innovation Solution
Development of humanized BCMA-specific chimeric antigen receptor (CAR) T cells using a humanized monoclonal antibody-derived single-chain variable fragment (scFv) linked with co-stimulatory domains, such as CD28 or 4-1BB, to enhance specificity and cytotoxic activity against BCMA-positive cancer cells while minimizing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cells are used to target BCMA, then antitumor activity is achieved, but specificity is reduced leading to off-target effects
Solution Approach 1:
The patent applies parameter changes by humanizing the antibody sequences (changing amino acid composition) to reduce immunogenicity while maintaining BCMA binding specificity. The humanized scFv sequences were engineered to have human-like framework regions while preserving the complementarity determining regions for specific BCMA recognition.
Solution Approach 2:
The patent creates a composite structure by combining the humanized scFv antigen-binding domain with co-stimulatory domains (CD28, 4-1BB) and signaling domains (CD3-zeta) to form a chimeric antigen receptor. This composite CAR structure integrates multiple functional elements to achieve both specificity and potent antitumor activity.
2Object-affected harmful factors
If humanized antibody sequences are used, then immunogenicity is reduced, but binding affinity may be compromised
Solution Approach 1:
The patent applies local quality by making only specific regions of the antibody humanized (the framework regions) while leaving the complementarity determining regions (CDRs) that are responsible for antigen binding largely unchanged. This localized humanization approach minimizes immunogenicity while preserving binding affinity.
Solution Approach 2:
The patent carefully adjusts the amino acid sequence parameters in the framework regions to achieve human-like properties while monitoring and maintaining the binding affinity parameters through selection and optimization of the humanized sequences.
3Power
If third generation CAR with multiple co-stimulatory domains is used, then cytolytic activity is increased, but cell complexity increases
Solution Approach 1:
The patent merges multiple co-stimulatory signaling domains (CD28 and 4-1BB) into a single CAR construct along with the antigen-binding scFv and signaling domains. This consolidation of multiple functional elements into one integrated receptor achieves enhanced cytolytic activity without requiring separate molecular components.
Data Source
AI summary
The present invention is directed to a humanized BCMA antibody or an antigen-binding fragment thereof, comprising VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. This humanized BCMA-CAR-T cells have specific killing activity against BCMA-positive tumor cells.