Clinical Impacts of Immunogenicity in Approved Antibody Drugs in Japan: A Quantitative Evaluation of Pharmacokinetics, Efficacy, and Safety Outcomes.

Immunogenicity, commonly manifested through the development of anti-drug antibodies (ADAs), is a critical concern for therapeutic antibodies as it can adversely affect pharmacokinetics (PK), efficacy, and safety. Although ADA-related impacts have been closely evaluated for individual antibody drugs, cross-product analyses of approved antibody drugs remain limited. In this study, we examined 92 antibody therapeutics approved by the Japanese regulatory authority as of March 2024, focusing on their review reports and prescribing information, to quantitatively assess the actual clinical impacts of ADA. Among these drugs, ADA-related decreased drug exposure, reduced efficacy, and worsened safety were indicated in the prescribing information of 18.5%, 10.9%, and 5.4%, respectively. Interestingly, ADA-related descriptions of both decreased drug exposure and reduced efficacy were observed in significantly lower proportions among oncology drugs than among non-oncology drugs. Furthermore, humanized antibodies exhibited higher proportions of ADA-related impacts than human antibodies; in particular, decreased exposure was significantly more common with humanized antibodies (27.7%) than with human antibodies (8.6%), supporting the concept that human antibodies have lower immunogenic potential. In addition, our evaluation of review reports indicated that all drugs with ADA-related reduced efficacy had decreased exposure. To the best of our knowledge, this is the first study to quantitatively evaluate the clinical impact of immunogenicity in approved antibody therapeutics in Japan. These results are expected to inform the appropriate clinical use of antibody therapeutics and contribute to a more comprehensive understanding of immunogenicity risk assessments during clinical development.