118: Assessment of Anti-Drug Antibody Incidence in Subcutaneously Administered Antibody-Based Therapeutics Approved Between 2010-2022

Statement of Purpose: The development of antibody-based therapeutics has revolutionized the treatment landscape of various diseases, but immunogenicity remains a concern. Subcutaneous (SC) administration has become popular in recent years given its potential to reduce patient burden and improve safety profiles, yet it may increase the immunogenicity risk compared to intravenous infusion, due to the increased exposure in the lymphatic system. New modalities like bispecific antibodies (BsAbs) and nanobodies add to this concern. The usefulness of non-human primate (NHP) in predicting clinical immunogenicity is limited by differences in binding epitopes and immunological responses in NHP vs human, affecting anti-drug antibody (ADA) formation. We hereby summarize the immunogenicity of SC-administrated antibody therapeutics approved between 2010-2022, with a focus on ADA incidence and its translatability from NHP to human.

Description of Methods & Materials: We conducted a systemic search for SC-administrated antibody therapeutics authorized by US Food & Drug Administration (FDA) or European Medicines Agency (EMA) between 2010 - 2022. For each product, available immunogenicity information from the FDA/EMA websites were collected, both human and NHP. Descriptive statistics were used to summarize the parameters of interest.

Data & Results: The analysis included 28 SC-administered antibody therapeutics developed for various indications, including immune-mediated inflammatory diseases (n=16), oncology (n=2), neurology (n=4), cardiovascular diseases (n=3) and rare/inherited disorders (n=4). Most (89%) products were monoclonal antibodies (mAbs), with over half being IgG1-based. Others included 2 BsAbs and 1 nanobody. Among these products, near 70% had an ADA incidence of < 10% (Figure 1A), with the highest rate of 23-78% for a humanized IgG2 mAb. Humanized antibodies had higher rates than human antibodies (median rate of 9.5% and 4.1% respectively), as expected. The 2 BsAbs and the nanobody had low rates of 0.5-5%. The presence of neutralizing antibodies (Nabs) with decreasing drug concentration may lead to a loss of efficacy for certain products, while the impact of immunogenicity on safety is generally limited (though definite conclusions cannot be drawn for some products due to data limitations). Out of the 25 products with data from both human and NHP, 14 (56%) had higher ADA incidence in NHP vs human (Figure 1B) and 2 had a lower incidence in NHP; 7 had < 10% rate in both NHP and human, 2 had comparable rates in both species (~ 11-13% or ~ 25%). Limitations of this analysis include possible underestimation of the overall ADA incidence for SC antibodies due to the lack of information on drugs that may show high incidence during development but not progress to approval; immunogenicity results may not be directly comparable across products, but current data may provide a general profile for these approved SC products; and the focus is on ADA incidence due to little public information of ADA titer and Nab.

Interpretation, Conclusion or Significance: Our analysis suggests that most SC-administrated antibody therapeutics approved between 2010 - 2022 have ADA incidence less than 5-10% in human. The immunogenicity observed in NHP cannot predict the ADA incidence in human (tends to overpredict), highlighting the need of reliable tools to identify agents with low immunogenicity risk in human.

Disclosures: The authors received no financial support in the writing of this Abstract.