Advances in Immunogenicity Risk Assessment, Monitoring and Mitigation of Biologics

Biologics have become essential medical treatments for many progressive, debilitating, or life-threatening diseases. In contrast to these benefits, their ability to trigger unwanted humoral and cellular responses has the potential to reduce their effectiveness or harm patients and, remains a challenge for drug developers and clinicians. In the case of life-saving therapeutics, the development of anti-drug antibodies (ADA) poses a serious threat. Indeed, in the case of the clotting-disorder Haemophilia A, protocols of de-sensitization to recombinant FVIII have been established to circumvent the drug’s immunogenicity by establishing antigen-specific tolerance. Of equal concern, the emergence of ADA or cellular immune responses against protein therapeutics and novel modalities such as gene therapy, gene editing and cellular therapy products can significantly impair treatment efficacy and result in loss of benefit to patients.

Consequently, to comprehend the underlying mechanisms of unwanted immunogenicity, design and implement mitigation strategies has become key to drug innovation. Over the past decades, the dramatic acceleration of biologics development provided opportunities to identify the numerous immunogenicity risk factors at play. Those are commonly referred to as product-, treatment- and patient-related risk factors. The capability to mitigate a risk inherently depends on its category. Whilst product-specific considerations exist, the ability to use loading doses, dose through, and apply comedication does happen, now with higher frequency in clinical trials. The establishment of validated methods to measure anti-drug cellular and humoral immune responses during clinical trials has enabled us to closely monitor patients for immunogenicity, identify any potential efficacy or safety issues and intervene early on. Approaches that induce tolerance to specific antigens have been successful in restoring immune tolerance to proteins used for therapy. Additionally, co-medication and/or co-administration of one or more biologics with immune-suppressive properties have proven to control the development of ADA and rescue life-saving drugs.

However, as not all treatments can be adjusted in the clinic, the main opportunities to reduce the immunogenicity risk present themselves at the drug design phase. The overall risk associated with a product depends on several of its features: 1) critical quality attributes such as its propensity to aggregate, likelihood to undergo post-translational modifications, presence of manufacturing process impurities that could act as adjuvants; 2) intrinsic immunogenicity of protein sequences determined by the presence of strong T cell epitopes; 3) capacity of RNA products to trigger the innate immune system; 4) pre-existing immunity to the protein, the viral vector such as AAV in gene therapy products, or part of the vector such as polyethylene glycol in lipid nanoparticle; 5) poly-specificity, which has also been shown to increase immunogenicity of monoclonal antibodies.

Over time, a suite of elaborate in silico and in vitro tools have been developed to assess these multiple product-related risks, compare lead compounds, and select drug candidates with the most favorable immunogenicity risk profile. These tools include prediction algorithms (epitope binding, epitope presentation, clinical immunogenicity, epitope foreignness), cell-based assays of multiple formats, and variable degrees of throughput and potential for automation. The creation of increasingly complex biologic modalities challenges academic and biopharmaceutical scientists to continually re-think existing tools to de-risk drugs by design, investigate new methods to monitor immune responses, and seek innovative approaches to mitigate immunogenicity in the clinic.

The aim of this collection is to provide readers with current advances in the field.

Solicited articles will highlight recent successes, discuss gaps, limitations and articulate how current thinking and knowledge and novel technologies including artificial intelligence, are driving continuous improvement of immunogenicity risk assessment, monitoring, and mitigation across all biologics modalities.

This collection focuses on:

• Immunogenicity of therapeutics, including but not limited to therapeutic proteins, cell, gene therapy, peptides and oligonucleotides-based products.
• Non-clinical immunogenicity risk assessment: in silico algorithms and prediction models, fit-for-purpose validation, standardization of in vitro assays, application of automation and high throughput approaches to in vitro tools, 3D in vitro systems
• Immunogenicity monitoring: novel quantitative analysis platforms, observed clinical immunogenicity, contribution to treatment decisions
• Clinical consequences of immunogenicity: loss of clinical responses, hypersensitivity, immune-complexes-related diseases
• Mitigation of immunogenicity: mitigation by design, antigen-specific and non-antigen-specific tolerance induction, combination therapies

All Topic Editors declare no conflict of interests