Small Modular ImmunoPharmaceutical (SMIP™) Molecules Directed at the TCR Complex (CD3) Block T Cell Activation and Cause Minimal Cytokine Release In Vitro (96.25)
| Autor: | Camilla Wang, Travis Beckett, Valerie Odegard, Scott Hussell, Ken Mohler, Catherine McMahan |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 184:96.25-96.25 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | SMIP molecules are single chain binding proteins based on a scFv-CH2-CH3 format. We have generated SMIP proteins using binding domains from well characterized mitogenic and non-mitogenic anti-CD3 antibodies, and have found dramatic differences in the biologic consequences on human T cells exposed to the compounds. In particular, compared to antibodies, SMIP proteins cause a unique Ca++ flux, are better able to down modulate the TCR complex from the cell surface, and can inhibit naïve and activated T cells in various in vitro assays. Importantly, SMIP proteins cause a much reduced level of cytokine release, notably, when compared to second generation anti-CD3 antibodies. Most known anti-CD3 antibodies cause activation of T cells, especially when cross linked via FcR on the surface of APCs. Without cross linking, these antibodies have minimal activation of T cells in vitro. In the clinic, second generation anti-CD3 antibodies are still plagued with cytokine release syndrome, despite showing little detectable cytokine release from primary T cells in vitro. We have developed an activated T cell blast assay sensitive enough to detect in vitro cytokine release caused by anti-CD3 antibodies in second generation formats. Results from these assays indicate that features in the SMIP format could generate novel CD3-directed therapeutics with superior efficacy and reduced potential for the serious side effects of Cytokine Storm. |
| Databáze: | OpenAIRE |
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