Pre-existing Antibody: Biotherapeutic Modality-Based Review

Abstract

Abstract. Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.

Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

“…Binding anti‐BIIB054 antibodies were detected at baseline in 2 participants who received placebo. Preexisting antibodies in patients without previous drug exposure are frequently observed for biotherapeutics and may represent an adaptive immune response following the exposure to antigens with structural similarities to the biotherapeutic …”

Assessment of Bezlotoxumab Immunogenicity

“…A total of 9 phase 3 participants had baseline ADA‐positive samples (non–treatment‐emergent positive) before dosing with bezlotoxumab, indicating the presence of preexisting antibodies. The origin of preexisting antibodies against biotherapeutic agents is often unknown, but they could result from previous exposure to a protein or glycan with a similar epitope to the drug . The impact of preexisting antibodies has not been well characterized in the literature, although most cases do not appear to have clinical consequences …”

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

“…The presence of neutralizing pre-existing antibodies against viral capsid proteins can block entry of the agents into targeted cells and preclude successful gene expression. For instance, the efficacy of adeno-associated virus (AAV)-based gene therapy can be impaired by the presence of neutralizing pre-existing antibodies to AAV proteins, of which anti-AAV2 serotype Abs were most prevalent across different regions, followed by antibodies to AAV1, AAV7, and AAV8 (8). A high prevalence of pre-existing antibodies to lentivirus has not been reported.…”

“…The pre-existing drug-reactive antibodies may be a part of the innate immune response of the host. Preexisting antibodies may have been arisen in response to xenobiotic environmental antigens unrelated to the drug, or due to a prior exposure to a homologous biologic drug (8). In contrast to the ADAs that are induced or boosted upon a biotherapeutic product treatment and show binding specificity to the biotherapeutic, pre-existing drug-reactive antibodies may bind to environmental and/or pathogenic antigens that have overlapping epitopes with multiple drug products.…”