Assessing Immunotoxicology During Drug Development: Highlights from a Webinar

Immunotoxicology assessment plays a large role in the drug development pipeline, especially for large molecules and biologics. Researchers in early drug development have a wide variety of immunologic assay methods available that can support research endpoints and offer opportunities for much clearer views into the efficacy and safety of a compound.

Aric Frantz, DVM, PhD, and Amanda Lucchini, PhD, from our Immunology and Immunotoxicology team, held a webinar where they discussed a number of immunologic assessment assays, such as immunophenotyping, T-Cell- Dependent Antibody Response (TDAR) and cell-based assays along with strategies available to drug development teams.

Immune System Cells at a Glance

As a collection of cells that are very diversified and diffused through the entire host, the immune system is incredibly complex, spanning across organ systems and tissue types. It has a myriad of components that have evolved into complementary, functional groups – innate and adaptive immunity – that balance speed with sophistication.

The innate immune system has developed pattern recognition and cells specialized in rapidly detecting foreign pathogens, antigens, bacteria, cells and viruses, while the adaptive immune system responds (more slowly) to new, novel threats, and has mechanisms for remembering how to fight those specific threats in the future.

Examples of the innate system cells include granulocytes (neutrophils, eosinophils, basophils), monocytes (macrophages and dendritic cells) and natural killer (NK) cells. The adaptive immune system cells, T and B cells, work together to identify and remember antigens and then produce antibodies.

Immunology’s Role in Pharmacology and Dose Setting

In the past, immunotoxicology often took a “weight-of-evidence approach” to identify potential threats to immune system safety during drug development. This evidence usually comes in the form of changes observed in anatomic or clinical pathology to immunological tissues, or parameters, respectively, or other clinical observations such as viral recrudescence, susceptibility to infection or increased incidence of tumors. All these effects tend to occur during or after initial evaluations and point back toward a previously unknown effect of the drug on the immune system.

Given that the negative effects become apparent relatively late in the research process, reliance on weight of evidence is costlier and can result in a slower, recursive research process. Additionally, a growing number of therapeutics are specifically designed to alter the function or prevalence of immune cells.

Immunology groups are now getting involved in the early stages in drug development – before a test article has ever been dosed into a preclinical model for safety assessment – to look at pharmacology and to understand dose-response relationships for biologic therapies that are designed from their outset to alter immune system function. The basic pharmacology of these test articles can be examined to determine whether there was a change in the number of immune effectors, the cytokines released or the amount of functional activity effectors possess when exposed to a new drug entity.

New Tools, New Opportunities

The continued development and refinement of immunology assays is producing alternatives to the historical weight-of-evidence approach. New assays allow for more in vitro and preclinical research into safety and efficacy and provide a better toolset for identifying unintended effects (or ruling out cause-effect relationships) throughout a drug development effort.

The assays most commonly used in immunotoxicology assessments fall broadly into three categories:

• Immunophenotyping – Looking at the immune-effector cells present in the blood and using tools such as flow cytometry to look at cell number and changes to the structures of cells.
• Plate-based assays (ELISA/ligand-binding) – Testing a tissue or fluid to determine the amount of a particular signaling molecule or immune system component in it.
• Cell-based assays – Placing testing agents directly on immune-effector cells or with other cells (if the test agent is also a cell), and then studying the results.

We offer a large and ever-growing number of assays to support drug development. Each new offering supports a new avenue of investigation. Drilling down into some of the available assay types, these tests can help answer potential questions such as:

• TDAR (T-Dependent Antibody Response): Is a test agent affecting the number of antibodies or the speed at which those antibodies are produced when the test system cell is exposed to a standard antigen?
• Natural Killer Cells: Is a test agent influencing the NK cells’ ability to find and kill infected cells?
• Phagocytosis: Is a test article influencing the ability of immune cells to swallow and digest foreign cells?
• Cytokines: Which ones are being secreted when an immune cell detects a particular antigen? Inflammatory ones? Suppressive ones? And in what amount?

Support for Different Purposes

Immunology assays can provide data that is highly valuable to planning a trial, such as how many of an immune-effector cell’s receptors are occupied by a particular test article at a particular dosage, and how that occupancy changes over time. This information can help researchers refine dosing amounts and frequencies for their trials. If two different dosages result in the same receptor occupancy, dosing might be adjusted for fewer off-target effects or better efficacy. If dosing frequency is occurring before a return to baseline, then dose-effect relationships are potentially being skewed as a test article accumulates over time.

If the intent of a drug is to modulate the immune system, immunotoxicology assessment can help support safety and pharmacology and check intended actions from in vitro work and early development studies to clinical work as part of looking for changes in the immune system.  These assays can help drug development teams investigate unexpected events, and in some cases, rule out the test article as cause of any downstream issues. 

As with many aspects of drug development, following ICH guidance can provide a foundation (ICH S6 and S8 are particularly relevant for immunology and Immunotoxicology) and working with experts in the field to tailor a solution to your drug development needs can help expedite the delivery of projects from discovery to market.

Want to learn more about how we can support your immunotoxicology assessment needs? Contact us here.