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Updated: May 9, 2026
Extraction of Tissue Antigens for Functional Assays
Published on: September 10, 2012
Prosthetic Antigen Receptors
Jingjing Shen1, Daniel A Vallera1, Carston R Wagner1
1†Departments of Medicinal Chemistry and ‡Therapeutic Radiology, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Abstract:
Chimeric antigen receptors (CARs) have shown great promise for the immunological treatment of cancer. Nevertheless, the need to genetically engineer a patient's T-cells has presented significant production and safety challenges. To address these issues, we have demonstrated that chemically self-assembled nanorings (CSANs) displaying single chain antibodies can bind to both the CD3 ε subunit of the T-cell-receptor/CD3 complex and the CD22 antigen on malignant B cells such as B-leukemias or lymphomas. We demonstrate that the multivalent and bispecific format allows the antiCD3/antiCD22 CSANs to stably bind to T-cell surfaces for greater than 4 days, while being easily disassembled on the cell membrane by treatment with the nontoxic FDA approved drug, trimethoprim. In the presence of CD22+ Raji cells, T-cells modified with antiCD3/antiCD22 CSANs were shown to selectively up-regulate the production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) and to initiate cytotoxicity. Taken together, our results demonstrate that antiCD3/antiCD22 bispecific CSANs offer a potential alternative to CARs, as prosthetic antigen receptors.
Insights
Chemically self-assembled nanorings (CSANs) offer a novel approach to cancer immunotherapy, acting as prosthetic antigen receptors. These bispecific CSANs target both T-cells and malignant B cells, triggering an immune response while allowing for safe, drug-induced disassembly.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- Chimeric antigen receptors (CARs) show promise for cancer immunotherapy but face production and safety challenges due to genetic T-cell engineering.
- Existing CAR T-cell therapies require complex genetic modification of patient T-cells, posing significant hurdles in manufacturing and safety protocols.
Purpose of the Study:
- To develop a novel, non-genetically engineered prosthetic antigen receptor system for cancer immunotherapy.
- To evaluate the efficacy and safety of chemically self-assembled nanorings (CSANs) as bispecific binders for T-cell engagement and cancer cell targeting.
Main Methods:
- Chemically self-assembled nanorings (CSANs) were engineered to display single-chain antibodies targeting the CD3 ε subunit on T-cells and the CD22 antigen on malignant B cells.
- The binding stability of antiCD3/antiCD22 CSANs on T-cell surfaces was assessed over time.
- The disassembly of CSANs from the cell membrane using trimethoprim was demonstrated.
- T-cell activation markers (IL-2, IFN-γ production) and cytotoxicity were measured in the presence of CD22+ cancer cells.
Main Results:
- AntiCD3/antiCD22 CSANs demonstrated stable binding to T-cell surfaces for over 4 days.
- CSANs could be effectively and safely disassembled from T-cells using trimethoprim.
- T-cells modified with CSANs showed selective IL-2 and IFN-γ production and initiated cytotoxicity against CD22+ B cells.
Conclusions:
- Bispecific CSANs represent a promising, non-genetically engineered alternative to CARs for cancer immunotherapy.
- CSANs offer a potentially safer and more readily producible platform for engaging T-cells against B-cell malignancies.
- The trimethoprim-inducible disassembly mechanism provides a controllable safety feature for this prosthetic antigen receptor system.
