Strategic Characterization of Anti-Drug Antibody Responses for The Assessment of Clinical Relevance and Impact

Abstract

All therapeutic proteins have the potential to induce anti-drug antibodies (ADA). Clinically relevant ADA can impact efficacy and/or safety of a biological therapeutic. Immunogenicity assessment strategy evaluates binding and neutralizing ADA, and the need for additional characterization (e.g., epitope, titer and so on) is determined using a risk-based approach. The choice of characterization assays depends on the type, application and immunogenicity of the therapeutic. ADA characterization can impact the interpretation of the risk profile of a given therapeutic, and offers insight into opportunities for risk mitigation and management. This article describes common ADA characterization methods. Strategic assessment and characterization of clinically relevant ADA are discussed, in order to support clinical options for safe and effective patient care and disease management.

An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

“…Under typical circumstances, subjects are expected to be immunologically tolerant to self-antigens, such as CD4. However, autologous antibodies can be induced against a variety of fully human biological agents that are used for therapy (39)(40)(41)(42)(43)(44)(45)(46). Depending on their epitope specificity, autoreactive anti-CD4 antibodies have been shown to mediate CD4 ϩ T cell depletion, suppression of T cell-dependent immune responses, or various other forms of immune dysregulation (47)(48)(49)(50)(51)(52)(53)(54), effects that define safety concerns for HIV vaccine testing.…”

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

“…ADA production affects clinical outcomes by impacting drug pharmacokinetics, and consequently its pharmacodynamics and efficacy profiles. The binding of ADAs to drugs depends on their affinities, dose, and duration of exposure 90, 91, 92…”

T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

“…Even fully human biotherapeutics have the potential for immunogenicity, and one important factor that might enhance potential immunogenicity is protein aggregation. [1][2][3][4][5][6][7][8][9] A particularly severe consequence of immunogenicity of a biotherapeutic is the rare development of antibody-mediated pure red cell aplasia (PRCA) in anemic patients treated with increased levels of aggregated forms of recombinant human erythropoietin (rhEPO).…”

“…1,2 Prediction of clinical immunogenicity on the basis of quality attributes of biopharmaceuticals or by utilizing preclinical in vitro and in vivo screening remain challenging. Even fully human biotherapeutics have the potential for immunogenicity, and one important factor that might enhance potential immunogenicity is protein aggregation.…”