title: 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.affiliation: †Departments of Medicinal Chemistry and ‡Therapeutic Radiology, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Shen
authors.affiliation: †Departments of Medicinal Chemistry and ‡Therapeutic Radiology, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
authors.affiliation: †Departments of Medicinal Chemistry and ‡Therapeutic Radiology, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Carston R
authors.initials: CR
authors.lastname: Wagner
mesh_terms: D018033:Antibodies, Bispecific / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation; D016207:Cytokines / Q000378:metabolism; D000067493:Dynamic Light Scattering; D005998:Glycine / Q000737:chemistry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods*; D011946:Receptors, Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016207:Cytokines; D005998:Glycine; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D052119:Lysosomal-Associated Membrane Protein 2; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; D051918:Sialic Acid Binding Ig-like Lectin 2; D013762:Tetrahydrofolate Dehydrogenase; D000099192:CD69 Antigens; C497867:CD22 protein, human; C508017:IL2RA protein, human