Bi-Specific CAR-T Cells Targeting EGFR and MUC1
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Solution Overview
Problem
Current CAR T cell therapies for NSCLC face limitations due to the lack of appropriate tumor-associated antigens and risks of on/off-target toxicities, which restrict their clinical efficacy.
Innovation Solution
Development of bi-specific CAR-T cells engineered to express anti-EGFR and anti-MUC1 binding agents, specifically using scFv fragments or aptamers, to target EGFR/MUC1-expressing cells, with a tandem or loop format CAR polypeptide structure that includes antigen binding domains, transmembrane, and co-stimulatory signaling regions, ensuring activation only upon binding to both antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy is applied to treat NSCLC, then anti-tumor activity is improved, but on/off-target toxicities occur due to lack of appropriate tumor-associated antigens
Solution Approach 1:
The patent combines two antigen-specific binding agents (anti-EGFR and anti-MUC1) into a single bi-specific CAR polypeptide structure. This merging allows the CAR T cell to recognize and bind to tumor cells expressing both antigens simultaneously, thereby improving target specificity and reducing off-target toxicities while maintaining anti-tumor activity.
Solution Approach 2:
The bi-specific CAR polypeptide is designed to perform multiple functions: it can bind to two different antigens (EGFR and MUC1) on the same tumor cell, providing enhanced specificity. This multi-functional design allows a single CAR T cell product to target a broader range of NSCLC cells while minimizing attacks on healthy cells that express only one of the two antigens.
2Ease of manufacture
If single antigen CAR T cells are used, then manufacturing is simpler, but therapeutic efficacy is limited due to antigen heterogeneity
Solution Approach 1:
The patent merges two antigen recognition domains into a single bi-specific CAR polypeptide, allowing the T cell to recognize tumor cells expressing both EGFR and MUC1 antigens. This approach overcomes antigen heterogeneity and loss of surface expression that limits single-antigen CAR T cell efficacy, while maintaining a manageable manufacturing process through single-vector transduction.
Data Source
AI summary
Bi-specific CAR-T cells are disclosed for treating NSCLCs. The disclosed CAR-T cells contain CAR polypeptides that can bind EGFR/MUC1-expressing cells. Therefore, also disclosed is an immune effector cell genetically modified to express an anti-EGFR CAR binding agent and an anti-MUC1 binding agent. Also disclosed are methods of providing an anti-tumor immunity in a subject with a EGFR and MUC1-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.