Prosthetic Antigen Receptors.

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.

• Authors: Jingjing Shen, Daniel A Vallera, Carston R Wagner
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 137 Issue 32 Pg. 10108-11 (Aug 19 2015) ISSN: 1520-5126 [Electronic] United States
• PMID: 26230248 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Antigens, CD
• Antigens, Differentiation, T-Lymphocyte
• CD22 protein, human
• CD3 Complex
• CD69 antigen
• Cytokines
• IL2RA protein, human
• Interleukin-2 Receptor alpha Subunit
• Lectins, C-Type
• Lysosomal-Associated Membrane Protein 2
• Receptors, Antigen
• Recombinant Fusion Proteins
• Sialic Acid Binding Ig-like Lectin 2
• Tetrahydrofolate Dehydrogenase
• Glycine

Topics

• Antibodies, Bispecific (metabolism)
• Antigens, CD (immunology, metabolism)
• Antigens, Differentiation, T-Lymphocyte (immunology, metabolism)
• CD3 Complex (immunology, metabolism)
• Cell Degranulation
• Cytokines (metabolism)
• Dynamic Light Scattering
• Glycine (chemistry)
• Humans
• Interleukin-2 Receptor alpha Subunit (immunology, metabolism)
• Lectins, C-Type (immunology, metabolism)
• Lymphocyte Activation (drug effects)
• Lymphoma, B-Cell (immunology, metabolism, pathology)
• Lysosomal-Associated Membrane Protein 2 (metabolism)
• Neutrophils (immunology, metabolism)
• Protein Engineering (methods)
• Receptors, Antigen (chemistry, genetics, metabolism)
• Recombinant Fusion Proteins (chemistry, pharmacology)
• Sialic Acid Binding Ig-like Lectin 2 (immunology, metabolism)
• Tetrahydrofolate Dehydrogenase (metabolism)