Key result
Intravenous staphylococcal protein A was administered to cynomolgus monkeys without observable toxicity at weekly doses up to 100 μg/kg, though antidrug antibodies decreased AUC by 54-76% by week 6.
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Intravenous staphylococcal protein A is well-tolerated in cynomolgus monkeys at weekly doses up to 100 μg/kg, supporting its clinical development as an immunomodulator despite the formation of antidrug antibodies.
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. Cmax 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 μg/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 μg/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 μg/kg.
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Bernton et al. (2014) studied this question. Intravenous staphylococcal protein A (SPA) was evaluated on Safety (NOAEL) and toxicokinetic profiles. Intravenous staphylococcal protein A was administered to cynomolgus monkeys without observable toxicity at weekly doses up to 100 μg/kg, though antidrug antibodies decreased AUC by 54-76% by week 6.
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