Impact of Antibody Fc Engineering on Translational Pharmacology & Safety: Insights From Industry Case Studies
Time: 10:30 am
day: Conference Day One
Details:
Balancing Efficacy and Safety through Fc Engineering:
• Fc engineering significantly alters antibody interactions with FcγRs and C1q, enabling enhancement or silencing of ADCC, ADCP, and CDC. These modifications, however, may also lead to undesired effects, such as inappropriate immune activation, cytokine release, platelet activation, and increased risk of thrombotic events. Hence, careful assessment of the pharmacology and potential safety concerns is critical in nonclinical models before clinical trials
Species Differences Influence Translational Pharmacology:
• Translational pharmacology is highly affected by species-specific differences in Fc receptor expression and function. Non-human primates closely resemble humans but lack certain human-specific receptors such as FcγRIIIB. Rodent models exhibit significant differences in receptor expression and function, complicating their predictive value for human responses. Thus, understanding species differences is essential for the choice and interpretation of nonclinical pharmacology and safety studies of Fcengineered monoclonal antibodies
Importance of Nonclinical Model Selection and Testing Strategy:
• Effective translation to clinical outcomes heavily relies on selecting appropriate nonclinical in vitro and in vivo models that accurately represent human Fc receptor biology and effector functions. The document emphasizes rigorous assessment strategies including receptor binding assays, effector cell-based assays, and cytokine release studies. Industry case studies highlight the necessity of a well-informed model choices, considering both pharmacological relevance and regulatory insights, to mitigate risks associated with Fc-modified antibodies
