Immunogenicity against therapeutic molecules, such as antibody drugs, is a clinical challenge in the successful treatment of many diseases. Therefore, immunogenicity risk assessment in preclinical settings will be useful to improve the efficacy and safety of products-based therapeutics in the development stages. As a first-class provider in the immunologic analysis fields, Creative Biolabs has established Sensitive Immunogenicity Assessment Technology® (SIAT®) system, with attention to in vivo models and assays used to mitigate this risk. Notably, we provide a variety of testing services to therapeutic protein immunogenicity risk assessment, which helps clients harvest more critical information on drug immune safety in the preclinical phase that could be valuable in the success of the drug.

Overview

Therapeutic antibodies and proteins may cause an immune response of bodies, leading to the occurrence of anti-drug antibodies (ADAs). Nowadays, therapeutic antibody drugs have significantly promoted the management of numerous chronic diseases and severe disorders. However, their optimal clinical application and further development are complicated by the induction of undesired immune responses. Therapeutic agent-induced ADAs can alter drug pharmacokinetics (PK) and pharmacodynamics (PD) resulting in impaired efficacy and occasionally safety problems. Over the past decade, a growing interest in investigating novel methods to assess the risk of unwanted immunogenicity during preclinical drug development, with the aim to reduce the risk upon the molecular design phase, clinical development, and when drug products reach the market.

SIAT® Immunogenicity Risk Assessment Services at Creative Biolabs

The purpose of immunogenicity studies is to characterize an immune response to the product and to identify correlations between ADAs and PK & PD, as well as efficacy & safety. As such, immunogenicity assessment should be contained in the planning of the key clinical trials, including the synchronization of sampling for ADAs and relevant biomarkers, if available, along with the evaluation of efficacy and safety.

Fig.1 The immunological cascade leading to ADA formation. (Tourdot, 2019)

Acquiring information on the immunogenic property of a drug prior to clinical trials is pivotal to avoid patient risks and attrition owing to costly drug failure. At Creative Biolabs, we bring a comprehensive meaning to immunogenicity and provide innovative services for preclinical immunogenicity risk assessment of therapeutic antibody drugs. Our current applicable strategies encompass in silico and in vitro methods to understanding the immunological risks associated with interactions of the treatment with crucial classes of immune cells (e.g. T cells, B cells, and antigen-presenting cells).

• Analysis of risk factors
  • Previous experience of the product/product class - If the product has an endogenous counterpart; if animal models provide useful data of potential results of immunogenicity; if there’s known antigenic sites of the drug.
  • Physicochemical and structural aspects - If there’re new possible immunogenic structures; expression construct and the posttranslational profile; stability and impurities; formulation and packaging pattern.
  • The route or the mode of administration.
  • Disease- and patient-related factors - State of the immunological tolerance (e.g. prone to autoimmune reactions; lack of immunological tolerance; concomitant immunomodulated therapy); pre-existing immunity (e.g. “natural” antibodies; antibodies due to previous therapy).
• Whole system analyses of risk
  • Animal models
    We have many animal species to quantitatively assess the risk of anti-drug immune response, including nonhuman primates, mice, mini-pigs, rodents, and so on. Of them, mice remain the most commonly used for immunogenicity studies.
  • Tissue damage models
    We offer a large range of human tissue models for testing drug-induced damage on vital systems, including cardiovascular system, ophthalmic system, nervous system, hepatic system, renal system, intestinal tissue, lung/airway tissue, and so on.
  • Mathematical models of prediction
    Predicting clinical outcomes by mathematical models is also common during drug development, with established approaches to simulating PK and PD outcomes through physiologically based PK and PK/PD modeling. The quantitative system pharmacology is brought together with systems biology and pharmacy to increase overall predictions of clinical outcomes.

Advantages

• One-stop, customized service package for immunologic projects
• A full suite of robust analysis of immunogenicity risk factors
• Multiple human tissue damage models for testing drug-induced damage
• Improved safety and risk prediction, as well as reduced investments in non-viable drugs

The planning and evaluation of immunogenicity risk of a biological product have been realized as multidisciplinary exercises. This risk assessment can evolve through the lifecycle of therapeutic protein and may be used to support applications at every step of product development. As an expert in the immune market, Creative Biolabs helps global clients decide the best way to assess immunogenicity of specific biologics using a series of advanced immunogenicity assays. For more information, please directly contact us or discuss with our experts today.

Published Data

• Immunogenicity Risk Assessment for Biotherapeutics Through In Vitro Detection

Fig. 2 Summary of clinical ADA frequency and percentage of positive responding donors as determined by in the CD134/CD137 T cell activation assay. (Sivan Cohen, 2021)

The study focuses on the immunogenicity risk assessment of biotherapeutics through the development of an in vitro method to measure activation markers CD134 and CD137 on CD4+ T cells. By examining the effects of 14 different biotherapeutics on peripheral blood mononuclear cells from 120 diverse donors, the research identified a correlation between clinical immunogenicity and the proportion of CD4+ T cells expressing CD134 and CD137. Biotherapeutics known for higher rates of anti-drug antibody (ADA) development demonstrated higher levels of these markers. This method provides a quick and effective preclinical test to evaluate the immunogenic potential of new biotherapeutics, enhancing the early screening process to eliminate candidates likely to cause ADA-related adverse effects. This approach is particularly critical in predicting and managing immunogenicity risks before clinical application, ensuring better safety and efficacy outcomes in therapy development.

FAQ

1. What is immunogenicity risk assessment for therapeutic antibody drugs?

   Immunogenicity risk assessment for therapeutic antibody drugs involves evaluating the potential for these drugs to elicit an undesirable immune response in patients. This assessment is crucial as it helps predict the development of anti-drug antibodies (ADAs) that can neutralize the drug's effects, alter its pharmacokinetics, and potentially lead to adverse clinical outcomes.

2. Why is immunogenicity risk assessment critical in the development of antibody drugs?

   It is critical because it informs key decisions throughout the drug development process, from molecular design to clinical trials. Identifying immunogenic risks early allows developers to modify drugs to reduce immunogenic potential, ensuring greater efficacy and safety, and reducing costly late-stage failures.

3. How is immunogenicity typically assessed in therapeutic antibodies?

   Immunogenicity is typically assessed using in vitro assays that detect the presence and magnitude of anti-drug antibodies in treated patients. Assays like ELISA, radioimmunoassays, and surface plasmon resonance are used to quantify ADAs, alongside cellular assays that can detect T-cell activation in response to the therapeutic antibody.

4. Can immunogenicity be completely eliminated in therapeutic antibodies?

   While it is challenging to completely eliminate immunogenicity, strategies like humanization of monoclonal antibodies, removal of T-cell epitopes, optimizing glycosylation, and controlling product-related impurities can significantly reduce the immunogenic potential of these therapies.

5. What are the consequences of high immunogenicity in therapeutic antibodies?

   High immunogenicity can lead to reduced drug efficacy as the immune system neutralizes the therapeutic effect, increased drug clearance, and potentially serious adverse reactions, including infusion reactions and anaphylaxis. It may also necessitate increased dosing or a switch to different therapeutic modalities.

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