Immunogenicity of Proteins Used as Therapeutics

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Background

Protein therapeutics provide critical medical interventions for many of the most complex and intractable diseases. Immunogenicity, the capacity of the protein therapeutic to elicit an undesired anti-drug antibody (ADA) response, is a key concern and is evaluated in the context of a patient focused risk-based assessment and by assays during clinical trials. Thus, immune responses to life saving therapeutics such as Enzyme Replacement Therapies (ERT) for Lysosomal Storage Diseases and Factor VIII for Hemophilia A constitute a severe risk necessitating mitigating strategies. Moreover, while ADA may not be life threatening, they can nullify the efficacy of therapeutics and sharply diminish patient quality of life. For example, within 5 years, 30-70% of patients receiving TNF-alfa inhibitor therapeutics experience “secondary failure” due to ADA. Similarly, about a quarter of hemophilia A patients develop ADAs to Factor VIII (known as inhibitors) leading to severely diminished quality of life and significant medical costs.

Additionally, exciting new medical interventions that hold immense promise in areas of unmet medical need may be limited in their applications due to immunogenicity. For example, novel gene-editing technologies, such as CRISPR-Cas may be limited by the presence of pre-existing antibodies and T-cell responses to the Cas9-protein, and gene therapies using AAV vectors can be similarly limited by the presence of preexisting immunity to the AAV capsid proteins.

The last decade has seen progress in basic and translational immunology that can help us better understand the generation and prevention of ADA to therapeutic proteins and gene therapies. The biopharmaceutical industry and regulatory agencies have developed and validated methods to identify and characterize immune responses to drugs during clinical trials. Other aspects of translational research are less mature but nonetheless have progressed considerably, including novel in silico, in vitro and ex vivo tools which can better predict the immunogenicity of therapeutic proteins, allowing for selection of the best candidates to enter the clinic. Such sophisticated prediction tools, together with high-throughput sequencing and HLA typing may allow prediction of which individuals are at high-risk of developing an immune response, thereby applying mitigation strategies in a targeted manner, and facilitate protein engineering for the “de-immunization” of highly immunogenic epitopes. In addition to predicting immunogenicity, there are established antigen targeted tolerance induction protocols that have proven highly effective in preventing or reestablishing immune tolerance to therapeutic proteins and several approaches for antigen specific immune-tolerance induction under active development.

The approaches described above have emerged in many different clinical settings and drug applications. The primary goal of this special issue is to consolidate the facets of the topic and in logical order: risk assessment, prediction, assays, and mitigation strategies. The articles solicited should be forward looking: what is the state of the art; an evaluation of the most promising approaches; and what can we expect in the near future? How can we ensure that the promise of current protein therapeutics is fully realized? More importantly, there are emerging products and therapeutic approaches with immense promise: how do we ensure that these are not stymied by immunogenicity?

Topic Editor Susan Richards is an employee of Sanofi and owns stock in the corporation. Topic Editor Bernard Maillere declares economic support from pharmaceutical companies (Novartis, Sanofi, and UCB) in the frame of collaborations aiming to evaluate the recognition by human T cells of therapeutic proteins and antibodies.

Keywords: anti-drug antibodies, drug development, immunogenicity, protein engineering, risk-assessment

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