Secondary failure: immune responses to approved protein therapeutics

Authors: Lagasse, HA; McCormick, Q; Sauna, ZE

Affiliations: US FDA, Lemostasis Branch, Div Plasma Prot Therapeut, Off Tissues & Adv Therapies,Ctr Biol Evaluat & Re, Silver Spring, MD 20993 USA.

Publication: Trends in Molecular Medicine ; 2021 ; 27. 1074–1083 December 2021

Abstract: Recombinant therapeutic proteins are a broad class of biological products used to replace dysfunctional human proteins in individuals with genetic defects (e.g., factor VIII for hemophilia) or, in the case of monoclonal antibodies, bind to disease targets involved in cancers, autoimmune disorders, or other conditions. Unfortunately, immunogenicity (immune response to the drug) remains a key impediment, potentially affecting the safety and efficacy of these therapeutics. Immunogenicity risk is routinely evaluated during the licensure of therapeutic proteins. However, despite eliciting anti-drug immune responses in at least some patients, most protein drugs are nevertheless licensed as they address unmet medical needs. The prelicensure immunogenicity assessments of therapeutic proteins are the subject of numerous reviews and white papers. However, observation and clinical management of the immunogenicity of approved therapeutic proteins face additional challenges. We survey the immunogenicity of approved therapeutic proteins, discuss the clinical management of immunogenicity, and identify the challenges to establishing clinically relevant immunogenicity assays for use in routine clinical practice.