Polyclonal Antibody Therapeutics: Analytical Innovations and Regulatory Perspectives for Addressing Heterogeneity Challenges.

Polyclonal antibodies (pAbs) are a cornerstone of the adaptive immune system, providing broad-spectrum protection by recognizing and neutralizing diverse antigens. Intravenous immunoglobulins (IVIg) derived from animal/human plasma are widely used to treat diseases such as primary immunodeficiencies, autoimmune neurological disorders, and situations requiring rapid immune protection, such as emerging infectious disease outbreaks. Compared with monoclonal antibodies (mAbs), pAbs offer several advantages, including faster, less technically demanding, and more cost-effective production, often directly from immunized animals or human serum. However, their complex, heterogeneous nature─reflecting the polyclonal response to multiple epitopes─creates significant challenges for characterization, quality control, and regulatory approval. pAbs have been underutilized in therapeutic applications due to the absence of robust, standardized analytical tools capable of fully assessing their heterogeneity. Conventional chromatographic and spectroscopic methods yield limited qualitative and quantitative information, insufficient for detailed structural and functional evaluation. This perspective highlights recent advances in high-resolution analytical technologies, particularly chromatographic and mass spectrometric approaches, that enable in-depth characterization of critical quality attributes (CQAs) of pAbs. These analytical strategies facilitate the assessment of parameters such as structural integrity, molecular size distribution, subclass composition, and polyclonality, which are crucial for ensuring product quality. Alongside these technical developments, regulatory frameworks for pAb-based therapeutics are evolving, emphasizing the need for standardized analytical criteria to ensure safety, efficacy, and batch-to-batch consistency. In our view, by integrating new analytical capabilities with clear regulatory expectations, pAbs can be more effectively developed as therapeutic agents, complementing mAbs and expanding the range of immunoglobulin-based interventions in clinical practice.