Humanized PSMA scFv CAR for Reduced Immune Rejection
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Solution Overview
Problem
Current CAR-T cell therapies, particularly those targeting prostate-specific membrane antigen (PSMA), face challenges such as immune rejection due to mouse-derived scFv regions and lack of long-term efficacy in treating solid tumors, limiting their therapeutic effect and making retreatment difficult.
Innovation Solution
Development of a humanized PSMA single-chain antibody (scFv) and a genetically modified chimeric antigen receptor (CAR) with enhanced specificity and affinity for PSMA, incorporating humanized codons and frameworks, along with a suicide-inducing fusion domain for controlled apoptosis, to improve compatibility and durability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse-derived scFv region is used in CAR-T cells, then antigen binding capability is achieved, but immune rejection occurs and long-term persistence is limited
Solution Approach 1:
The patent applies parameter changes by humanizing the scFv region through amino acid sequence modification. The mouse-derived scFv sequence is mutated to contain humanized codons and framework regions, changing the immunogenic parameters of the antigen-binding domain. This allows the CAR-T cell to maintain PSMA binding capability while reducing recognition by the human immune system, thereby improving long-term persistence and reducing immune rejection.
Solution Approach 2:
The patent creates a composite structure by combining humanized scFv sequences with human T-cell signaling domains in a single chimeric antigen receptor. The humanized VH and VL regions are connected via a linker peptide to form a hybrid antibody fragment that integrates foreign antigen-binding functionality with human cellular compatibility, resolving the conflict between non-human antigen recognition and human immune acceptance.
2Reliability
If humanized scFv with humanized codons and frameworks is used, then compatibility and reduced immune rejection are achieved, but the complexity of CAR construction increases
Solution Approach 1:
The patent segments the CAR structure into distinct functional modules: the humanized scFv antigen-binding domain, the transmembrane domain, and the intracellular signaling domain. The humanized scFv itself is segmented into VH and VL regions connected by a standardized linker. This modular segmentation allows for systematic construction and optimization of the CAR while maintaining compatibility, as each module can be independently designed and assembled.
Data Source
AI summary
Provided are an anti-PSMA single-chain antibody, a chimeric antigen receptor associated therewith and use thereof. An amino acid sequence of a heavy chain of the anti-PSMA single-chain antibody includes a sequence shown in SEQ ID NO: 1, and an amino acid sequence of a light chain of the anti-PSMA single-chain antibody includes a sequence shown in SEQ ID NO: 2. The anti-PSMA single-chain antibody is a humanized scFv antibody of PSMA, is more functional in the human body, has better compatibility, and is less prone to be rejected by the immune system. The chimeric antigen receptor has better response effects after specifically bonding to PSMA so that CAR-T cells generate a stronger immune response to tumors, and the chimeric antigen receptor also has better long-term effectiveness than other PSMA chimeric antigen receptors.