Abstract
Drugs formulated from monoclonal antibodies (mAbs) are clinically effective in various diseases. Repeated administration of mAbs, however, elicits an immune response in the form of anti-drug-antibodies (ADA), thereby reducing the drug's efficacy. Notwithstanding their importance, the molecular landscape of ADA and the mechanisms involved in their formation are not fully understood. Using a newly developed quantitative bio-immunoassay, we found that ADA concentrations specific to TNFα antagonists can exceed extreme concentrations of 1 mg/ml with a wide range of neutralization capacity. Our data further suggest a preferential use of the λ light chain in a subset of neutralizing ADA. Moreover, we show that administration of TNFα antagonists result in a vaccine-like response whereby ADA formation is governed by the extrafollicular T cell-independent immune response. Our bio-immunoassay coupled with insights on the nature of the immune response can be leveraged to improve mAb immunogenicity assessment and facilitate improvement in therapeutic intervention strategies.
Highlights
More than 30 years since the approval of the first therapeutic monoclonal antibody for clinical use, the therapeutic monoclonal antibodies (mAbs) market has expanded exponentially, establishing mAbs as one of the leading biopharmaceutical therapeutic modalities [1]
Recovered IFX-F(ab’)2 purity was evaluated by SDS-PAGE (Figure 1B) and ELISA (Figure 1C) to ensure that the IFXF(ab’)2 exhibits no traces of IFX-Fc/undigested IFX that will contribute to the background level when using anti-Fc HRP conjugate at the detection phase
A major shortcoming of their use is the development of ADA in patients receiving the mAb
Summary
More than 30 years since the approval of the first therapeutic monoclonal antibody (mAb) for clinical use, the therapeutic mAb market has expanded exponentially, establishing mAbs as one of the leading biopharmaceutical therapeutic modalities [1]. The molecular mechanisms that lead to the induction of ADA are not wellunderstood and were initially thought to be related to the murine origin of the mAbs because they were recognized as “non-self ” by the human immune system. This idea propelled the mAb discovery field to focus on engineering refined mAbs by reducing the non-human portions and developing chimeric, humanized, and fully human mAbs by using human libraries or humanized mice at the mAb discovery phase [7]
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