Abstract
The development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in some cases even reverse such deleterious immune responses. CD4+ T cells are essential players in the development of most ADAs, while memory B-cell and long-lived plasma cells amplify and maintain these responses. This review summarizes methods to predict and experimentally identify T-cell and B-cell epitopes in therapeutic proteins, with a particular focus on blood coagulation factor VIII (FVIII), whose immunogenicity is clinically significant and is the subject of intensive current research. Methods to phenotype ADA responses in humans are described, including T-cell stimulation assays, and both established and novel approaches to determine the titers, epitopes and isotypes of the ADAs themselves. Although rational protein engineering can reduce the immunogenicity of many biotherapeutics, complementary, novel approaches to induce specific tolerance, especially during initial exposures, are expected to play significant roles in future efforts to reduce or reverse these unwanted immune responses.
Highlights
The administration of biological drugs to patients, especially serial exposures to treat chronic conditions, carries a risk of eliciting anti-drug antibodies (ADAs) [1,2,3]
The identification of reliable predictive biomarkers would allow rational, evidence-based criteria for deciding which patients are likely to benefit from transient immunosuppression therapies during biotherapeutic administration. This non-comprehensive review focuses on several current approaches, dilemmas and novel techniques to profile ADA responses and mitigate their impact on the translation of promising biotherapeutics
I have focused here on studies of clinical samples obtained from patients and normal healthy controls, rather than animal model studies, in part because immunogenicity in humans is often not predicted by animal testing
Summary
The administration of biological (e.g., protein) drugs to patients, especially serial exposures to treat chronic conditions, carries a risk of eliciting anti-drug antibodies (ADAs) [1,2,3]. The antibodies were detected and the trial halted before titers increased to significantly impact hemostasis Another sequence-modified rFVIIa variant was tested in a separate trial, and the immune response of one patient who developed ADAs evaluated; interestingly, subsequent epitope mapping indicated that this subject’s PBMCs responded to synthetic peptides having the wild-type FVIIa sequence, but not to peptides corresponding to the modified amino acid sequence [18]. Multiple exposures to a foreign antigen, especially in context of inflammation or innate immune signaling (“danger”), can prime and boost the host immune response, resulting in production of high-affinity, high-titer, class-switched antibodies This essential defense mechanism, is an unwanted or even adverse event when activated in response to a biotherapeutic intended to treat a clinical disorder. Further T-cell stimulation with inflammatory cytokines generates signal 3, promoting T-effector proliferation and secretion of cytokines and chemokines, especially in germinal centers where B cells are activated and proceed to differentiate into antibody-secreting plasma cells and memory B cells
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