title: Cross-reactive and pre-existing antibodies to therapeutic antibodies--Effects on treatment and immunogenicity.
abstract: The potential for immunogenicity is an ever-present concern during the development of biopharmaceuticals. Therapeutic antibodies occasionally elicit an antibody response in patients, which can result in loss of response or adverse effects. However, antibodies that bind a drug are sometimes found in pre-treatment serum samples, with the amount depending on drug, assay, and patient population. This review summarizes published data on pre-existing antibodies to therapeutic antibodies, including rheumatoid factors, anti-allotype antibodies, anti-hinge antibodies, and anti-glycan antibodies. Unlike anti-idiotype antibodies elicited by the drug, pre-formed antibodies in general appear to have little consequences during treatment. In the few cases where (potential) clinical consequences were encountered, antibodies were characterized and found to bind a distinct, unusual epitope of the therapeutic. Immunogenicity testing strategies should therefore always include a proper level of antibody characterization, especially when pre-formed antibodies are present. This minimizes false-positives, particularly due to rheumatoid factors, and helps to judge the potential threat in case a genuine pre-dose antibody reactivity is identified.
authors.affiliation: a Sanquin Research; Dept. Immunopathology; Amsterdam, The Netherlands; and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam ; Amsterdam , The Netherlands.
authors.forename: Karin A
authors.initials: KA
authors.lastname: van Schie
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
mesh_terms: D000906:Antibodies / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D003429:Cross Reactions; D006801:Humans
chemical_list: D000906:Antibodies
keywords: ADA, anti-drug antibody; CDR, complementarity-determining region; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumor necrosis factor; VH, variable heavy; VL, variable light; allotype; anti-drug antibodies (ADA); glycan; idiotype; immunogenicity; pre-existing antibodies; rheumatoid factor