Protein therapeutics may elicit an anti-therapeutic antibody (ATA) response in patients. This response depends on a number of factors including patient population, disease state, route of delivery or characteristics specific to the product. Therapeutics for immunological indications often target relatively young and healthy patients with hyperactive immune systems who have periodic flares and remissions. The hyperactive immune system of these patients can add several levels of bioanalytical complexity due to the presence of cross reactive molecules such as autoantibodies. In addition, the long-term chronic dosing regimen often necessary in this patient population can increase their risks of immunogenicity against the therapeutic and lead to safety concerns. Therefore, development of a sensitive and drug-tolerant ATA method is important. Bridging ATA assays are usually very sensitive and drug-tolerant methods for immunogenicity assessment; however these methods are particularly vulnerable to any factor that is able to bridge the conjugated therapeutics used as reagents and can generate false positive signal. Although there are many potential interfering factors in serum, rheumatoid factors (RFs), autoantibodies associated with rheumatoid arthritis (RA), are of particular concern in this type of assay. MTRX1011A is a non-depleting anti-CD4 monoclonal antibody therapeutic that was clinically tested in RA patients. This paper will discuss the bioanalytical challenges encountered during development of a clinical ATA assay for MTRX1011A. These challenges highlight interference due to patient disease state, in this case presence of RF in RA patients, as well as specific molecule-related interference caused by an engineered mutation in the Fc region of MTRX1011A designed to enhance its binding to the neonatal Fc receptor (FcRn). We will discuss the characterization work used to identify the cross-reactive epitope and our strategy to overcome this interference during development of an effective ATA assay to support clinical evaluation of MTRX1011A.
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