Abstract
Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug’s pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug’s therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.
Highlights
In the last three decades, the pharmaceutical industry experienced a massive shift toward the use of protein drugs, often referred to as “biologics.” Biologics offer higher specificity and better characterized mechanisms of action compared to small molecule drugs, and their use has revolutionized the treatment of a wide range of diseases and disorders
Other monoclonal antibodies (mAbs), including the anti-HER-2 trastuzumab, block receptor-ligand interactions to achieve a desired effect, either by blocking the receptor domain to inhibit an activation signal by removing a soluble ligand entirely from circulation [6]. mAbs can induce fragment crystallizable (Fc)-dependent effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are important for the anti-CD20 drug obinutuzumab that is used for the treatment of lymphoproliferative disorders [7]
We recently found that repeated administration of infliximab results in a vaccine-like response, where anti-drug antibodies (ADAs) formation is governed by the extrafollicular T cell-independent immune response [96]
Summary
In the last three decades, the pharmaceutical industry experienced a massive shift toward the use of protein drugs, often referred to as “biologics.” Biologics offer higher specificity and better characterized mechanisms of action compared to small molecule drugs, and their use has revolutionized the treatment of a wide range of diseases and disorders. MAb humanization often significantly reduces immunogenicity and ADA formation [24]. Of the immune responses, including in the formation of ADAs following immunization and administration of mAbs. Monoclonal antibodies immunogenicity is mainly manifested in ADA generation [49].
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