885-P: IND-Enabling Assessment of Tolerance and Safety for SAB-142—A First-in-Class Fully Human Polyclonal Antithymocyte Immunoglobulin to Delay the Progression of Type 1 Diabetes

SAB-142, a human polyclonal anti-thymocyte immunoglobulin, is currently being evaluated for safety in a Phase 1 clinical trial for Type 1 Diabetes (T1D). Previous clinical studies showed that Thymoglobulin^TM, a rabbit polyclonal anti-thymocyte immunoglobulin (rATG), significantly slowed the progression of T1D. However, rATG is highly immunogenic and causes serum sickness limiting redosing over time. Our objective is to develop a safer and efficacious immunomodulatory agent to delay the progression and/or onset of T1D. Here we demonstrate the preclinical safety and tolerance of SAB-142 in Cynomolgus macaques, as well as in vitro safety and activity assays. For in vitro assays, binding of SAB-142 to human serum proteins and Glomerular Basement Membrane (GBM) antigen was assessed by ELISA. Platelet and red blood cell (RBC) binding was determined by flow cytometry and hemagglutination assays, respectively. A single dose of SAB-142 (1, 5, and 10 mg/kg), and rATG (5 mg/kg) as an active comparator, were infused intravenously to groups of 6 macaques, which were monitored for 4-weeks post-infusion. Clinical scoring was performed; blood and tissue samples were analyzed. SAB-142 bound below detection limits to human serum proteins and GBM in vitro. As compared to rATG, SAB-142 had higher platelet binding, but lower binding to RBCs. In macaques, SAB-142 and rATG were equally well tolerated, and no adverse effects were observed. All monkeys maintained normal body weight and ability to thrive. Despite reduced white blood cell counts, as expected by both reagents, no bleeding or thrombotic complications were observed post-infusion. ECG, hematology, coagulation, urine analyses and metabolic parameters were normal during and post-infusion. At the end of the study, no pathological findings were observed in native organs. Our results indicate that SAB-142 is well tolerated and should be immunomodulatory in humans.