Studies of the Safety, Pharmacokinetics and Immunogenicity of Repeated Doses of Intravenous Staphylococcal Protein A in Cynomolgus Monkeys

Abstract

Three Good Laboratory Practice safety studies were performed with intravenous injections of highly purified staphylococcal protein A (SPA) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. These studies established a no-observable-adverse-effect level (NOAEL) for up to 12 weekly doses of SPA, as well as toxicokinetic profiles for SPA, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C-reactive protein (CRP), troponin I and the change in the blood absolute lymphocyte count (ALC) 24 hr after SPA dosing. The transient decrease in ALC noted at 24 hr after dosing was similar to that seen in human Phase 1 trials. The majority of active-treated monkeys developed antibodies against SPA. C max was not affected by development of antidrug antibodies (ADAs), and after the first dose was 87 (SD 19) ng/mL, 330 (SD 84) ng/mL and 1191 (SD 208) ng/mL for 5, 25 and 100 lg/kg doses, respectively. The development of ADAs increased plasma clearance of SPA. By the sixth weekly dose, the AUC was decreased by 76%, 54% and 66% for the 5, 25 and 100 lg/kg dose groups, respectively. These results indicate that SPA can be administered intravenously to non-human primates without observable toxicity at weekly doses of up to 100 lg/kg.

The potential of bacterial anti-phagocytic proteins in suppressing the clearance of extracellular vesicles mediated by host phagocytosis

“…IdeS can achieve rapid consumption of IgG while do not induce long-term suppression of protective antibodies, demonstrating good safety and tolerability (84). As for other candidates, for example, SpA from S. aureus, assessment of its in vivo safety has been conducted in mice, monkeys and human beings respectively, none of which reveals any safety issues (85)(86)(87). Therefore, we believe that the combination of bacterial anti-phagocytic proteins with EVs holds considerable potential in enlarging the therapeutic application of EVs, with IdeS further standing out as a most preferred candidate due to its excellent safety and tolerability.…”

Construction of a versatile fusion protein for targeted therapy and immunotherapy

“…Spa is safe in crab-eating monkeys (Bernton & Haughey, 2014) and has been effectively utilized in the treatment of idiopathic thrombocytopenic purpura (ITP) disease (Kapur et al, 2018). Thus, we chose the C domain of Spa (SpaC) as a basic structural unit to establish a versatile protein complex and constructed the sequence of a fusion protein, named SpaC Catcher or SpaCC for short, which consisted of a SpyCatcher domain labeled with 6-His, a protein linker, and the C domain of Staphylococcal protein A (Figure 1a).…”