![]() ![]() Chimeric antibodies were developed by replacing the murine constant domains by human constant domains. 1 This led to the development of methods to include human sequence in antibody therapeutics, and thus potentially reduce immunogenicity. The first monoclonal antibody to be approved for therapeutic use, OKT3, was a murine antibody that was found to be highly immunogenic. Therapeutic monoclonal antibodies in particular may be the target of such pre-existing antibodies, as will be elaborated in this review. ![]() These antibodies have been suggested to potentially induce adverse effects or diminish treatment efficacy, and are even believed by some to contribute to or be predictive of future loss of response due to immunogenicity. One issue that has gained considerable attention in recent years is the occasionally reported presence of pre-existing antibodies, which can bind to a drug already in treatment-naive individuals. The accurate prediction and assessment of (clinically relevant) immunogenicity remains a challenging endeavor. 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. Immunogenicity testing strategies should therefore always include a proper level of antibody characterization, especially when pre-formed antibodies are present. In the few cases where (potential) clinical consequences were encountered, antibodies were characterized and found to bind a distinct, unusual epitope of the therapeutic. Unlike anti-idiotype antibodies elicited by the drug, pre-formed antibodies in general appear to have little consequences during treatment. 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. However, antibodies that bind a drug are sometimes found in pre-treatment serum samples, with the amount depending on drug, assay, and patient population. Therapeutic antibodies occasionally elicit an antibody response in patients, which can result in loss of response or adverse effects. The potential for immunogenicity is an ever-present concern during the development of biopharmaceuticals. ![]()
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