Evaluating ADA Response Essential for Biologics

Regulatory Recommendations for Investigating the Immune Response to Biologics

Understanding the intricacies of biologics, including the ability to trigger unwanted immune responses, is crucial for modern drug development. Biologics are produced from natural sources, including but not limited to viruses, vaccines, monoclonal antibodies, toxins, antimicrobial agents.

Biologics are a staple of the pharmaceutical industry; however, regulatory expectations are growing.

The FDA and other world health authorities recommend pharmaceutical companies investigate the immune response to biologics, given that the immune response can negatively affect safety and efficacy, underscoring the necessity of nonclinical and clinical assessments of immunogenicity during the drug development process.

The use of immunogenicity assessments is expected to lead to safer and more effective treatments. Navigating the challenges of immunogenicity is warranted, given that regulatory authorities expect immunogenicity assessments to lead to improved patient outcomes. The knowledge gained from assessing immunogenicity will ultimately be key to the future success of biologics.

Definition and Process of Immunogenicity

Immunogenicity has a specific meaning in the pharmaceutical industry, that is, the ability of a drug product to provoke an adaptive immune response in humans or animals.

Immune cells, which are types of white blood cells, have the potential to recognize the drug product as non-self. If this occurs, immune cells respond to the drug as if it is a threat and then act to remove the drug. Immunogenicity begins with antigen-presenting cells (APCs) taking up the biologic upon entry.

The APC processes the antigen and presents it to CD4+ T cells. T cells with the correct receptor can recognize specific antigens, which leads to T cell proliferation.

T cells and B cells coordinate together, which allows the generation of antibodies to neutralize and eliminate the biologic. The extent and type of interactions affect the immunogenicity process.

Patients’ biological makeup, status, history of medication and immune system interactions, and the biologic’s characteristics all affect immunogenicity, particularly due to the fact that every patient’s immune system is unique. It is, therefore, important to investigate immunogenicity before a biologic reaches the market.

The Critical Importance of Immunogenicity Assessments

Immunogenicity assessments are paramount; the immune response has the potential to adversely affect the efficacy and safety of the drug product. It is therefore crucial to begin investigating immunogenicity early during drug development and continue the assessment throughout the development process.

Immunogenicity includes the generation of anti-drug antibodies (ADA), which are undesirable antibody molecules produced by plasma cells to counteract the biologic. Other immune responses include cellular responses, but the pharmaceutical industry mainly focuses on ADAs.

Neutralization is a common type of ADA response. The ADAs, in this case, are neutralizing antibodies (nAbs) that bind in close proximity to the active site of the biologic, blocking its functional activity.

Neutralization can reduce the efficacy of the biologic. If the biologic has a physiologically important counterpart in the body, the ADA response can potentially neutralize the endogenous molecules, which can cause long-lasting adverse effects.

ADA responses to biologics can lead to many possible immediate and long-term adverse events. Immediate adverse reactions, such as anaphylaxis, can be life-threatening. Some adverse reactions may be mild, such as injection site reactions and dermatitis, but can interfere with a subject’s quality of life.

Clearly, there are potential risks of ADA related to pharmacokinetics (PK), pharmacodynamics (PD), safety and efficacy. In this context, it is incumbent that marketing applications include a comprehensive and rigorous evaluation of ADA. An Integrated Summary of Immunogenicity (ISI) is an ADA evaluation that provides an overview of the effects of ADA on the drug product and the subjects receiving the drug.

Concerns regarding safety and efficacy highlight the importance of using immunogenicity assessments throughout the drug development process.

Definition and Structure of an Integrated Immunogenicity Summary

An Integrated Summary of Immunogenicity (ISI) provides a summary of the immunogenicity profile of a biologic. Understanding the immunogenicity profile of a biologic is key for determining its risk. A thorough understanding enables alignment with regulatory expectations early in drug development.

The ISI contains four sections:

1. Analysis of Risk Factors. The product/product class, physical and chemical makeup, dosing regimen, disease features, and patient characteristics can all affect immunogenicity. This section explores the impact of these factors.
2. Risk-based Immunogenicity Program. A section detailing the bioanalytical strategy, other experimental approaches, and summarizing the clinical study design.
3. Immunogenicity Results. This section mainly explores the relationship between ADA, PK, PD, safety, and efficacy.

This section also characterizes the ADA response. This includes incidence, prevalence, titers, nAb prevalence, and sometimes domain specificity, which is the part of the molecule eliciting the ADA response.

4. Conclusions on the Risk of Immunogenicity. This section explores immunogenicity in terms of clinical benefit and risk. A risk mitigation plan is also a key part of this section.

Role of an Integrated Summary of Immunogenicity in Biologics

FDA Guidance recommends using ISIs to span from Phase 1 through the BLA and to post-approval stages of development.

However, many pharmaceutical companies have limited expertise with immunogenicity assessments and the regulatory expectations for characterization and reporting.

Bioanalysis & Biomarker and Quantitative Clinical Pharmacology services at Amador Bioscience, however, have the expertise, capabilities, and experience needed for ISIs and related matters.

Amador’s ISI expertise can aid pharmaceutical companies in identifying risk early during drug development and proposing risk mitigation strategies, which is important for regulatory submissions and also enables the creation of monitoring and control measures.

ISIs are mainly detailed in the CTD Module 5.3.5.3 Reports of Analyses of Data from More than One Study. Modules 2.7.2.4 Special Studies and 2.5.3 Overview of Clinical Pharmacology may also include information from the ISI.

Regulatory agencies do not require a standard format for an ISI; however, they expect a complete and adequate assessment of how the ADA data impacts PK, PD, safety, and efficacy. The assessment should explore ADA effects on populations, sub-populations, and individuals.

Beginning an ISI early in clinical drug development enables the document to be updated through development to post-marketing.

Future Use and Importance of Immunogenicity

The safety and effectiveness of biologics can be affected by immunogenicity. Regulatory agencies recommend ISIs as an important part of submissions.

Expertise with ISIs is critical for biologics. Amador’s experience with ISIs can help ensure a quality risk assessment as well as help mitigate risks.

With new and improved biologics on the horizon, immunogenicity must be assessed in a timely manner during drug development, which will allow for the prompt evaluation of immunogenicity risks for a new biologic product. Additionally, with appropriate mitigation strategies, the ISI can play a pivotal role in improving the technical and regulatory odds of a successful product.

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