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Preclinical Drug Development: Evaluating the Immune System from Discovery to Safety

The immune system is extraordinarily complex. It consists of immune cells, tissues, organs, and a whole host of other substances and factors that help the body fight off infection, remove abnormal cells, and maintain overall homeostasis.

This webinar provided information relevant to immune system evaluation in preclinical drug development. Some of the topics were:

  • Immune system components
  • How immune responses develop
  • States of immune dysregulation
  • Therapies that affect the immune system
  • How immunotherapies have changed the landscape
  • Methods used to evaluate immune responses including immunotoxicology and immunopathology
  • Data integration, weight-of-evidence, and regulatory considerations

Importantly, to gain a deep, meaningful understanding of immune system changes that occur in drug development, the immune system must be evaluated throughout every stage of the development process—from discovery to safety.

If you were unable to attend the webinar’s live session, keep reading for a high-level recap of the topics discussed. You can also watch a recording of the webinar here.

Where is the immune system located?

The immune system is comprised of cells, soluble factors, and physical tissue components that are present within every organ of our bodies. This includes immune organs such as the thymus, bone marrow, spleen, and lymph nodes and non-immune organs such as the liver, lungs, and brain. Information about changes in the immune system can be gleaned from evaluating these various organs.

What are the characteristics and components of the immune system?

The immune system is functionally dynamic and highly responsive with variability in overall responses seen  between individuals, species, and across populations. In addition, environmental influences, previous exposures, disease state/co-morbidities and therapies can all affect immune responses.

There are two primary arms that make up the immune system: Innate immunity and adaptive immunity.

  • Innate immunity: This is the first line of defense characterized by a rapid, non-specific response that lacks  a memory response
  • Adaptive immunity: This is a  catered immune response that takes time to develop, is typically specific to an antigen appropriate to a threat, and often generates a memory response.

The webinar describes these characteristics and components of innate and adaptive immunity.

Can disease states cause immune dysregulation?

Yes, a disease state can influence immune responses. For example, cancer triggers an immunosuppressive response which dials down the normal anti-tumor immune response. Chronic inflammation can result in a state of immune stimulation or immune exhaustion.

When dysregulation occurs, the assumptions of a “normal” immune response may no longer be valid. This means a therapy may not work the same in a patient with a disease like it otherwise might in a healthy patient.

Do therapies affect the immune system?

Many factors affect the immune system. Vaccines, immunotherapies, new drugs, chemicals, medical devices, and other factors can all affect the immune system. While some therapies can simply have an expected effect on the immune system due to how they’re designed, chemical structure, or their mechanism of action, others are specifically designed to modulate the immune system (e.g., biologics, small molecules, vaccines, etc.).

The creation of these immunomodulatory therapies such as monoclonal antibodies and cell-based therapies have become more widespread in the last decade, especially cancer immunotherapies, and the specialized immunotherapies bring unique challenges for evaluating the immune system.

Immunomodulatory therapies add complexity when evaluating:

Since these therapies are designed to modify the immune system, it can be very challenging to determine when intended pharmacology moves to exaggerated pharmacology and with the variability in immune responses, when these changes represent toxicity.

What is immunotoxicology and immunosafety?

Immunotoxicology is a field that largely began in the 1970s to address concerns that chemicals and therapies had potential harmful effects on the immune system. Over the years and with numerous therapies that modify immune responses but may not be specifically toxic, it became important to understand the nuanced ways the immune system was affected. Immunosafety is the comprehensive evaluation of potential (toxic) effects on the immune system .Evaluating immunosafety occurs throughout the entire drug development pipeline and is conducted to understand the full spectrum of effects as opposed to just overt toxicity.

While critical, immunosafety assessment is also challenging because of:

  • The dynamic, responsive, and redundant nature of the immune response
  • Variability in immune responses in individuals and population (wide range of normal)
  • The effects age, sex, co-morbidities, therapies, and other factors have on an individual’s immune system
  • The non-static nature of immune responses (they change over time, during a response, etc.)
  • A lack of defined criteria to measure when effects become “toxic” (this is especially true with immunotherapies)

How are immune responses evaluated?

Evaluation methods for assessing an immune response can be grouped in four key categories:

Diagnostics/clinical signs

This includes running diagnostic tests on any number of biomarkers to look for clinical signs that indicate an effect on or change in the immune system, such as a rise in cytokine or antibody levels.


This involves the use of:

  • Immunophenotyping to analyze cell populations and subpopulations based on the expression of specific markers. Cells routinely evaluated include T cells, B cells, and NK cells.
  • Cytokine/chemokine profiling to evaluate serum levels or cell-specific production. This method utilizes the cytokine release assay, an in vitro assay that uses human cells to predict the potential for cytokine release in vivo.
  • Other Immunotoxicology assays that measure immune cell and immune system characteristics and functions.

Clinical pathology

There are numerous clinical pathology assays that can be run. Some of these include the following:

  • Complete blood cell count tests
  • Bone marrow smears/aspirate tests/biopsies
  • Complement system analyses
  • Clinical (serum) chemistry tests
  • Coagulation profiles
  • Urinalyses

The complete blood cell count and bone marrow evaluation are the most commonly used clinical pathology assays that provide information on immune system changes.

Anatomic pathology

The use of anatomic pathology to evaluate immune response often includes reviewing:

  • Survival and mortality
  • Macroscopic (gross) findings
  • Organ weights
  • Microscopic (histopathologic) findings
  • Correlations to other findings variably included (e.g., clinical pathology results, immunotoxicology, etc.)

Additional specifics these evaluation methods and microscopic appearances of various immune and non-immune organs are provided in the webinar.

How (and why) to evaluate immune effects in drug development

The best way to understand most fully the changes in the immune response is through the integration of the information provided by the evaluation methods described above (Diagnostics/clinical signs, Immunology/immunotoxicology, Clinical pathology, and Anatomic pathology). The more data that can be provided and evaluated together, the better the picture and our understanding of the immunopathogenic processes and effects that a drug can have on the immune system. Ideally, the evaluation of any new therapeutic, chemical entity, or medical device should occur throughout the entire drug development progress, from discoveries at the bench, through preclinical studies, and into the patient populations. Only then can we accurately and confidently answer the following questions:

  • Does this new therapeutic, chemical entity, or medical device work?
  • Is it safe?
  • Do its benefits outweigh its risks?

How does evaluating immune system response throughout drug development impact regulatory review?

By evaluating changes to the immune system in every stage of drug development, you can collect and integrate data from many disciplines into a consolidated and singular understanding.

This continuous evaluation is part of a “weight of evidence” approach, which can include data from any combination of the four evaluation methods. And while it requires an understanding of the immune system and the significance of study-related effects, as well as communication between scientists from different fields of expertise, it can benefit a product when undergoing review.


Watch the webinar to learn more about the importance of evaluating immune system responses in drug development. Or, if you’re ready to learn how StageBio partners with you for your immunology needs, go here.

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