Pre-Existing Biotherapeutic-Reactive Antibodies: Survey Results Within the American Association of Pharmaceutical Scientists

Abstract

The immunogenicity profile of a biotherapeutic is determined by a multitude of product and patient-related risk factors that can influence the observed incidence and clinical consequences of immunogenicity. Pre-existing antibodies, i.e., biotherapeutic-reactive antibodies present in samples from treatment-naïve subjects, have been commonly observed during immunogenicity assessments; however their relevance in terms of the safety and efficacy of a biotherapeutic is poorly understood. An American Association of Pharmaceutical Scientists-sponsored survey was conducted to gather information about the prevalence, nature, and consequences of pre-existing antibodies in clinical and nonclinical studies. The survey results indicate that pre-existing antibodies against a variety of biotherapeutics (e.g., mAbs, fusion proteins) are frequently encountered, especially in the context of autoimmune diseases, but that the methods and approaches used to detect, characterize, and report these antibodies vary. In most cases, pre-existing antibodies did not appear to have clinical consequences; however, a few of the respondents reported having observed an effect on pharmacokinetic, pharmacodynamic, safety, and/or efficacy parameters. The findings from this survey are an important first step in evaluating the potential risks associated with the presence of pre-existing antibodies and highlight the importance of standardizing the approaches for detection and characterization of these antibodies. Cross-industry sharing of case studies and relevant data collection will help better inform biotherapeutic risk/benefit profiles and provide deeper understanding of the biological consequences of pre-existing antibodies.

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

“…Several reports describe pre-existing reactivity from antidrug antibody (ADA) assays in baseline samples collected from treatment-naïve subjects (1)(2)(3)(4)(5)(6)(7). This pre-existing reactivity can be due to the presence of antibodies from treatment-naïve subjects or due to other non-antibody interferents.…”

“…A prior survey conducted and published by the Therapeutic Product Immunogenicity Focus Group (TPIFG) of the American Association of Pharmaceutical Scientists (AAPS) indicated that despite the broad experience in encountering pre-existing drug-reactive antibodies in treatment-naïve samples, the impacts of these antibodies are still largely unknown (3). The survey revealed a variety of approaches that are currently employed to detect, characterize, and mitigate the impact of pre-existing reactivity including pre-existing antibodies in ADA assays.…”

A Phase 1 Dose‐Escalation Study of ASP2409, a Selective T‐Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy

“…The presence of preexisting ADAs is not uncommon, especially in autoimmune diseases. 19 About 85% of patients tested positive for ADAs after single-dose administration of ASP2409, which is considerably higher than the reported incidence for abatacept (2%-3% incidence). 20 Higher ADA incidence for ASP2409 relative to abatacept could be explained by a number of factors including: (1) greater number of amino acid changes in the CTLA-4 domain, (2) differences in the Fc fusion sequence, (3) differences in assay sensitivity, and (4) differences in dosing regimen (abatacept ADA incidence was measured at therapeutic dose levels, which are immunosuppressive).…”

Pre-existing Antibody: Biotherapeutic Modality-Based Review

“…Matrix components that are present in drug-naïve samples and capable of generating ADA like signals may be referred to as preexisting reactivity. Pre-existing reactivity is heterogeneous by nature and is comprised of various types of matrix components including those that facilitate drug intermolecular interactions (19)(20)(21). Below are some examples of matrix components that could cause pre-existing reactivity in ADA assays:…”

“…Although pre-Ab responses pose an immunogenicity risk, it is difficult to know whether existence of pre-Abs can promote treatment-boosted ADAs and lead to clinical adverse events (19). This manuscript provides a review of the nature of various pre-existing anti-drug antibodies reported for a wide variety of biotherapeutic modalities.…”