Biotherapeutics, including cell- and gene therapies, have become a core component of treatment strategies for a wide diversity of diseases.  However, all biologic agents are immunogenic, in the sense that they can provoke an undesirable immune response. Immunogenicity of therapeutics is difficult to predict in patients, and the potential consequences range from no clinical significance to diminished efficacy of the treatment, hypersensitivity reactions, such as infusion reactions, or breaking of tolerance and autoimmunity. 

“We’re seeing products that are much more powerful, but at the same time, associated with higher complexity” Paul Chamberlain, Advisory Board member at NDA says. “The therapeutic window, where it’s safe to operate is becoming more and more narrow. That is why we more than ever need to understand the risks associated with these molecules”.

Immunogenicity was considered as being a potential obstacle for the development of biosimilar medicines. However, the earlier concerns have not materialized into an incremental risk because the risk factors were understood and then effectively controlled.

“Because the bioanalytical assays used have relatively high sensitivity, Paul Chamberlain says, the results of these assays must be interpreted in relation to relevant clinical endpoints to assess impact on overall clinical benefit versus risk for a particular therapeutic indication. Actually, this need for an “integrated” approach is the primary motive for my work”.

The extent of manifestations of undesirable immunogenicity depends on an unpredictable relationship between intrinsic (i.e. molecular structure) and extrinsic (mode of action, systems biology, subject and disease-related variables, conditions of use and product quality) factors. Patients treated with biologics frequently develop anti-drug antibodies (ADAs) whose presence can be a concern of forthcoming treatment failure. The development of ADAs is influenced by a multitude of factors, either related to the patient, the treatment, or to the product itself. Although many of the immunogenicity risk factors are understood, immune responses to biologics cannot be predicted based solely on characterization of these factors or in non-clinical models but must be evaluated in the clinic.

Comprehensive immunogenicity testing throughout all phases of development reveals a biotherapeutic’s potential to create an immune response – however these critical assessments are anything but one-size-fits-all. A risk-based approach is required to balance the potential harm with potential good of a new biotherapeutic in clinical development and allows investigators to provide a rationale for the proposed immunogenicity testing, based on product- and patient-specific concerns. Understanding the mechanisms for immunologically related adverse events enables the development of strategies to help mitigate their risk.

“Fortunately,” Paul Chamberlain continues,” today there are a number of risk minimization tools that can be applied before developing investigational biotherapeutic candidates, allied to highly effective methods for evaluating the immune response during pre-clinical and early clinical development”.

A successful outcome, according to Paul Chamberlain, depends on input from a multi-disciplinary team of development scientists applying an integrated strategy from the earliest stages of product development. The initial immunogenicity risk assessment sets the bearings for this integrated approach, which can then be refined as development proceeds.

“My interest in this exercise was driven by experience gained while supporting an investigational therapeutic protein which was discontinued due to the development of auto-reactive antibodies in a Phase 2 clinical study. Arguably, the consequences may have been foreseen and avoided by application of the ISI, risk-based approach that was initially articulated by Dr Amy Rosenberg at the FDA”.

As immunogenicity testing needs to be conducted throughout the development process, the use of a living document that can be easily incorporated into the common technical document (CTD) is desirable. The Integrated Summary of Immunogenicity is a document that links the risk analysis to the immunogenicity evaluation. To start the documentation early in product development and update as the clinical program progresses is the most advantageous strategy to avoid rate limiting delays – and failures – caused by unexpected results.

”In my view”, Paul Chamberlain says, “the process should commence at the lead candidate selection stage by creating a ‘living’ summary that serves to identify pertinent risk factors, and an action plan for evaluation and mitigation that is aligned with the potential severity of consequences of clinically impactful immunogenicity”.

Presenting the Integrated Summary of Immunogenicity in Clinical Trial Applications and Scientific Advice meetings supports the review process and represents the full story of how the relevant risks have been evaluated and mitigated for the product. It can help define priorities for product quality control, choice of bioanalytical methods and clinical study design.

“Sometimes, sponsors leave it too late, resulting in an incomplete dossier or, worse, unexpected results in pivotal clinical studies” Paul Chamberlain says. “In 80 per cent of the cases, I come in late in the process, and then, it’s much more difficult. By addressing these issues from the very beginning, those problems would not appear in the first place”. 

For the investigator or physician, the most important consideration is that appropriate risk mitigation measures have been applied to avoid immune-mediated adverse events or loss of treatment response. The extent of risk mitigation provisions is informed by a thorough risk assessment that takes into account the “worst-case” situation, i.e. subjects who may have the highest probability of developing serious consequences.

“The major challenge for regulators is uncertainty”, Paul Chamberlain explains. “The purpose of the Integrated Summary of immunogenicity is to provide the regulator with the complete story to enable a suitably informed decision about the impact of immunogenicity on overall clinical benefit versus risk”.

While the concept of an integrated assessment of immunogenicity risk has been around for quite some time, guidance from EMA (2017) and FDA (2019) have now embraced the ISI format that NDA has been submitting since 2009.

“Regulators are enthusiastic to receive the ISI as a detailed, self-standing document of the CTD format”, Paul Chamberlain says. “Additional transparency and completeness of information submitted in the dossier has led to a marked diminution in the number of questions arising during the MAA or BLA review”.

While many companies are now developing processes to facilitate an integrated approach, there remains a belief that the immunogenicity risk level can be categorised in an a priori manner, that is before thorough clinical evaluation has been completed, which is unfortunate according to Paul Chamberlain. Subjective categorization can be restrictive since the perception of risk may change according to the amount of information available.

“From my perspective”, Paul Chamberlain concludes, “the objective is to ask the pertinent questions early enough in the process to reduce risks for developability and approvability. This fits with the fundamental regulatory philosophy – understanding risks means controlling risks”.