title: Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction.
abstract: Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.
authors: Molecular Therapies Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
authors: Fabio
authors: F
authors: Turatti
authors: Mariangela
authors: M
authors: Figini
authors: Emanuela
authors: E
authors: Balladore
authors: Paola
authors: P
authors: Alberti
authors: Patrizia
authors: P
authors: Casalini
authors: James D
authors: JD
authors: Marks
authors: Silvana
authors: S
authors: Canevari
authors: Delia
authors: D
authors: Mezzanzanica
mesh_terms: D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D007135:Immunoglobulin Variable Region; D018719:Erb-b2 Receptor Tyrosine Kinases; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human