Chimeric Antigen Receptor Binding Unit for Solid Tumor Targeting
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Solution Overview
Problem
Current CAR T cell therapies face challenges in effectively targeting and reducing solid tumors due to difficulties in identifying specific antigens and achieving effective killing of tumor cells without harming normal tissues.
Innovation Solution
Development of an antigen binding unit comprising a light chain CDR and a heavy chain CDR that specifically binds to a WT1 peptide complexed with HLA, with minimal non-specific binding to reference peptides, used in a chimeric antigen receptor (CAR) to induce cytotoxicity in cells expressing WT1, enhancing specificity and efficacy in targeting cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy is used to target solid tumors, then tumor cell killing capability is improved, but specificity to tumor cells versus normal tissues deteriorates
Solution Approach 1:
The patent applies local quality by designing the CAR with specialized components: the antigen binding unit is engineered to recognize specific tumor-associated antigens (such as WT1, MAGE-A3, NY-ESO-1) with high affinity, while the costimulatory domains (CD28, 4-1BB) provide localized activation signals. This localized functional differentiation ensures that the CAR T cells selectively target and kill tumor cells expressing these antigens while sparing normal tissues that lack antigen expression or express them at low levels.
Solution Approach 2:
The patent employs parameter changes by optimizing the CAR structure with variable domain configurations (such as (VH-VL)2 or VH-VL arrangements), adjusting affinity constants (KD values), and modifying costimulatory domain compositions. These parameter optimizations enable the CAR to achieve higher specificity and affinity for tumor antigens, improving tumor cell killing while reducing off-target effects on normal tissues.
2Adaptability or versatility
If broad antigen targeting is used to treat various solid tumors, then adaptability to different tumor types is improved, but binding specificity to tumor antigens deteriorates
Solution Approach 1:
The patent applies universality by creating a modular CAR platform that can target multiple different tumor-associated antigens including WT1, MAGE-A3, NY-ESO-1, and others. The standardized CAR structure with interchangeable antigen binding units allows the same basic design to be adapted across different cancer types (ovarian, lung, breast, colorectal, pancreatic cancers), providing broad applicability while maintaining high specificity through antigen-selective binding units.
Solution Approach 2:
The patent uses segmentation by dividing the CAR into distinct functional modules: antigen binding units (with heavy and light chain variable regions), hinge regions, transmembrane domains, and intracellular signaling domains. This modular segmentation allows independent optimization of each component, enabling the antigen binding unit to be specifically tailored for high-affinity binding to particular tumor antigens while the rest of the CAR structure remains standardized for broad applicability across different tumor types.
Data Source
AI summary
Disclosed herein are methods of treating a subject exhibiting a cell that expresses Wilms tumor protein 1 (WT1). The methods typically utilize anti-WT1 antigen binding units or chimeric antigen receptor immunoresponsive cells to a subject in need thereof to effect killing of tumor cells.