Preclinical Target Animal Safety Evaluation of Veterinary Monoclonal Antibodies: Principles, Methods, and Interpretation.

Abstract

Monoclonal antibodies (mAbs) represent a rapidly expanding pharmaceutical class in veterinary medicine, with several products now authorized for use in dogs and cats. Limited published articles and veterinarian exposure to the principles of drug development present challenges in interpreting published safety evaluations that inform product labeling and clinical use. This review describes the principles, methods, strengths, limitations, and interpretation of preclinical target animal safety (TAS) studies for veterinary mAbs and is intended to equip veterinarians and researchers with the knowledge to critically evaluate published TAS data and understand how preclinical safety evidence translates to product labeling. TAS studies are conducted in healthy, purpose-bred animals of the target species using a margin of safety (MOS) approach with supratherapeutic dosing to screen for product risks. The regulatory and scientific framework is based on internationally harmonized guidance for safety evaluation of small molecule therapeutics in veterinary medicine and more than four decades of experience with mAb therapeutics in human medicine. The high target specificity of the mAb drug class enables a hypothesis-driven evaluation strategy, combining standard endpoints with target-informed specialized assessments. Terminal gross and histopathological endpoints provide safety data that clinical studies cannot generate, identifying potential adverse effects down to the cellular level. Unique to veterinary medicine, these data are generated directly in the target species. Data interpretation follows a weight-of-evidence approach in which findings are presumed treatment-related until demonstrated otherwise, integrating dose-response relationships, biological plausibility, and both study and historical control data. TAS studies complement the broader safety evaluation continuum, including clinical field studies, pharmacovigilance, and independent research.