LAUSR

Purpose Biologic molecules constitute a major part of the therapeutics portfolio across the pipeline of several biotech and pharmaceutical companies. They have the advantage of being more target-specific, and recent progress in protein engineering has allowed product designs on various platforms that befit the therapeutic indication and allow differentiation from competitor molecules. They are fundamentally large proteins, with complex structural heterogeneity arising from production using recombinant gene technology in cell lines. These biotherapeutics run the risk of being recognized as foreign by the host immune system, eliciting both B and T cell responses. The impact ranges from none to benign infusion reactions to life-threatening anaphylaxis, and with evolving modalities for such molecules in the pipeline, it is critical to understand the interplay of various risk factors that modulate the immune response. During risk assessment and mitigation strategies in drug development, risk factors are broadly classified arising from patient and product-related origins, and this review will focus on the product-related risk factors. Methods A basic primer on immune mechanisms underlying immunogenicity to a biotherapeutic is provided to highlight those aspects that are influenced by product attributes; this is followed by a more focused discussion of relevant and recently published works pertaining to each critical product attribute and the in vitro and in vivo methodologies utilized to assess their risk. Results Some product-related factors have an influence on the product’s immunogenicity. This varies with the type of biotherapeutic product, the disease background, and the diversities seen in the subjects. Conclusion This article highlights some of the experimental limitations on risk evaluation of individual product attributes and emphasizes that immunogenicity manifesting as an undesirable clinical outcome results from the cumulative effect of several risk factors.