Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

Abstract

Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.

Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches

“…This can lead to altered pharmacokinetics, reduced clinical efficacy and an increased risk of adverse events (AEs). 5 As authority-approved biosimilars and their reference medicines contain essentially the same active substance, it is reasonable to assume that there will be no difference in how a patient's immune system reacts to the two medicines upon switching. 6 Nevertheless, the risk of enhanced hypersensitivity or anaphylactic reactions remains a key concern among physicians.…”

“…All biologics have the potential to trigger an immune response, which primarily manifests as the production of antidrug antibodies (ADAs). This can lead to altered pharmacokinetics, reduced clinical efficacy and an increased risk of adverse events (AEs) . As authority‐approved biosimilars and their reference medicines contain essentially the same active substance, it is reasonable to assume that there will be no difference in how a patient's immune system reacts to the two medicines upon switching .…”

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

“…The immunogenicity of biotherapeutics may also be an important issue. Anti-drug antibodies (ADA) may be generated and have detrimental impact on drug safety, efficacy and pharmacokinetics (Smith et al, 2016).…”

Immunogenicity and skin clearance recapture in clinical studies of brodalumab

“…5,6 ADAs may compromise efficacy (including retreatment efficacy) and safety profiles of a drug by altering its pharmacokinetic/pharmacodynamic profile. 7,8 For example, ADA formation can enhance drug clearance, and neutralizing antibodies can prevent the agent from binding to the target receptor. 8 ADAs have also been associated with hypersensitivity and immune reactions, and localized injection site inflammation may precede such reactions.…”