title: Preclinical support for combination therapy in the treatment of autoimmunity with atacicept.
abstract: Atacicept, a fully human recombinant fusion protein that blocks the activity of BLyS (B-Lymphocyte Stimulator) and APRIL (a proliferation-inducing ligand), is undergoing clinical evaluation in B-cell-mediated diseases, including autoimmune disorders. Nonclinical studies in mice and cynomolgus monkeys demonstrate dose-dependent, reversible decreases in circulating Ig concentrations and reductions in mature B cells in the peripheral blood and lymphoid tissues. However, the combination of atacicept with purine synthesis inhibitors (e.g., mycophenolate mofetil [MMF]) and anti-B-cell monoclonal therapy (e.g., rituximab) has not been evaluated. Atacicept does not augment hematological toxicities associated with MMF, including anemia or thrombocytopenia. Combination of atacicept with MMF or rituximab reduced B cells in the periphery (MMF) or tissues (MMF and rituximab) further than did monotherapy, as was the case with atacicept-MMF combination therapy and serum Ig concentrations. Overall, atacicept appears to augment the pharmacologic activity toward B cells of current immunosuppressive therapies without increasing the hematological toxicities associated with MMF. Enhanced reduction in B cells and Ig concentrations associated with atacicept combination therapy may increase therapeutic activity or allow dose reduction in autoimmune patients. Findings from nonclinical safety studies support clinical evaluation of atacicept combination therapies.
authors.affiliation: ZymoGenetics, Inc., Seattle, WA 98102, USA. info@zgi.com
authors.forename: Rafael
authors.initials: R
authors.lastname: Ponce
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001402:B-Lymphocytes / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D007074:Immunoglobulin G / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D000069283:Rituximab; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D009173:Mycophenolic Acid; C524618:TACI receptor-IgG Fc fragment fusion protein