A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety
| Autor: | Catherine A. Fleener, Dawn K. Stetsko, Patricia M. Davis, James K. Tamura, Steven G. Nadler, Haiqing Wang, James William Bryson, Ruth Brosius, Plummer Christopher, Steven Grant, Theodora W. Salcedo, Olga Ignatovich, Lumelle A. Schneeweis, Suzanne J. Suchard, Selena Kansal, Zheng Yang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.drug_class
T cell T-Lymphocytes Immunology Antigen-Presenting Cells chemical and pharmacologic phenomena Pharmacology Lymphocyte Activation Antibodies Autoimmune Diseases CD28 Antigens medicine Immunology and Allergy Animals Humans CTLA-4 Antigen Receptor Cell Proliferation CD86 Chemistry Antagonist CD28 hemic and immune systems Receptor antagonist Macaca fascicularis medicine.anatomical_structure B7-1 Antigen B7-2 Antigen Ex vivo CD80 |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 191(9) |
| ISSN: | 1550-6606 |
| Popis: | Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4–mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell–dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases. |
| Databáze: | OpenAIRE |
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