Non-clinical safety evaluation of XOMA 3AB, a novel triple antibody drug product targeting botulinum toxin type A, in Sprague-Dawley rats

AB is being evaluated for the treatment and prevention of botulinum toxin type A (BoNT/A) poisoning. XOMA 3AB is composed of an equimolar mixture of three human or humanized IgG1 monoclonal antibodies (mAb), referred to as NX01, NX02 and NX11, that target unique non-overlapping regions on BoNT/A. These antitoxin mAbs bind to BoNT/A resulting in rapid clearance of the toxin from the systemic circulation. Nonclinical safety evaluation pharmacokinetics (PK) and toxicology studies were conducted in Sprague-Dawley rats to support the clinical development of XOMA 3AB. The PK of XOMA 3AB was evaluated in rats for 71 days following a single intravenous injection at dose levels 0.1, 1 and 10 mg/kg. XOMA 3AB was administered weekly for five weeks by intravenous injection at doses up to 50 mg/kg and by intramuscular injection at a dose level of 3 mg/kg for toxicology assessment. Parameters evaluated included clinical observations, food consumption, body weights, clinical pathology, ophthalmology, urinalysis, macroscopic and microscopic evaluation. Bioanalytical assays were developed using an electrochemiluminescence (ECL) format to measure the individual mAbs in rat serum. An ECL assay was also developed to measure total anti-drug antibodies to XOMA 3AB. The results show that NX01, NX02 and NX11 have similar PK profiles and demonstrate a dose proportional bi-exponential decline in initial and terminal half-lives, clearance and volume of distribution. The half-lives of NX01, NX02 and NX11 ranged from 12.4 to 17.2 days. Animals with anti-drug antibodies showed increased clearance of XOMA 3AB from the serum. There were no toxicologically significant findings related to administration of XOMA 3AB to rats. The no-observable-adverse-effect level (NOAEL) following intravenous administration was ≥ 50 mg/kg, the highest dose tested.