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Dr. Arno Kromminga
Posted by Dr. Arno Kromminga BioAgilytix Insight, Immunogenicity

Influencers in the Assessment of Immunogenicity, Part 1: The Basics of Immunology

Influencers in the Assessment of Immunogenicity, Part 1: The Basics of Immunology

In order to discuss the challenges and implications surrounding immunogenicity in depth, it is advantageous to have an understanding of the immunological network. Immunology and the study of immunogenicity have been the focus of most of my career, and the past decades have taught me that the immune system has impressive capabilities that can either be a challenge, or that can be harnessed to help those of us working in drug development.

The Purpose of the Immune System
The immune system is an incredibly intricate system of compounds and cells, with the primary purpose to defend the body against endogenous and exogenous threats, such as infections. Consider this: most people generally perceive genetics to be one of the most complex areas of study; however, humans only have about 30,000 genes. In comparison, each person has billions upon billions of immune system elements like antibodies, T-cell receptors, and other compounds. Compounding this complexity is the fact that there are two main types of immunity present in the human body: innate immunity and adaptive immunity. Both play a major role in defending the body from a diverse set of threats and maintaining an immunological homeostasis.

Innate Immunity
The first line of defense in the immune system is a battery of components of the innate immunity. The innate immune system is always “on” and can be effective in immediately eliminating threats, as well as initiate adaptive immune responses to provide increased protection against threats. Innate immunity is basically made up of three subdivisions of processes – anatomical, humoral, and cellular – which are used to carry out its defensive functions.

Anatomical or mechanical barriers to infection begin with epithelial surfaces. The skin and mucosa act as our first line of defense against invading organisms. Certain structures of the body are also specifically designed to keep it free from harmful microorganisms, including, for example: movement due to cilia or peristalsis; the flushing action of tears; and the trapping effect of mucous membranes. Additionally, compounds associated with these processes, like the lysozyme and phospholipase found in tears, assist in making these processes more effective.

Humoral barriers to infection, in effect, “back up” the anatomical barriers and are very effective in preventing colonization of tissues by microorganisms when the anatomical barriers fail and foreign antigens begin to penetrate healthy tissue, as often indicated by inflammation. The complement system is the major humoral non-specific defense mechanism. When this part of the defense process goes into effect, it leads to the needed increase in vascular permeability, recruitment of phagocytic cells, and lysis and opsonization of bacteria. Another major humoral compound of the innate immunity is a family of antimicrobial peptides called defensins, which are widely expressed in a variety of epithelial cells and sometimes in leukocytes, playing an important role due to their antimicrobial, chemotactic, and regulatory activities.

On a cellular level, part of the inflammatory response is the recruitment of macrophages to the sites of infection or threat. The macrophages function in the intracellular killing of microorganisms. Macrophages also work to repair tissue and act as antigen-presenting cells, which are needed for the introduction of adaptive immune responses. Another component of the cellular innate immunity is phagocytosis, which is activated by the attachment to molecular structures known as pathogen-associated molecular patterns (PAMPS).

Adaptive Immunity
The second line of defense in the immune system is the acquired or adaptive immunity. While these defenses may take days to weeks to respond to a primary invasion, this system is able to produce antibodies and cell-mediated responses that allow the body to recognize antigens, adapt the defense strategy, and eliminate the threat. Adaptive immunity not only deals with small-time threats like bacteria or viruses; it also recognizes endogenous compounds needed to maintain an immunological balance, which may result in the destruction of threatening cells such as tumor cells.

The adaptive immune system not only produces antibodies with different functionalities, but also utilizes lymphocytes to attack viruses and other pathogenic structures. Lymphocytes are mainly divided into two types of cells: B cells and T cells. Adaptive humoral immunity is mediated by antibodies produced by differentiated B-lymphocytes while cell-mediated immunity is arbitrated by T-lymphocytes.

B cells produce antibodies designed specifically to attack dangerous antigens. Often these compounds are foreign (bacterial or viral antigens), although sometimes they are threatening but endogenous (which may lead in extreme to autoimmune disorders). The highly diverse population has the ability to recognize millions of antigens, even those that have never been introduced to the body before or are brand new manufactured biologics. When faced with an unwelcome antigen, B cells, with the support of T cells, bind to antigens and then alter themselves to become plasma cells that have the capabilities to make the antibodies needed to combat the (foreign) antigen. In addition to creating antibodies, they can also become memory B cells, designed to respond even more forcefully if the same antigen invades the body in the future.

T cells have different functionalities: while helper T cells assist in the destruction of pathogens, or interact with and induce the activation of B cells to produce antibodies, cytotoxic T lymphocytes (CTL) directly attack invaders by binding to pathogenic cells structures via highly adaptive T cell receptors. This induces cytotoxic reactions, which in turn causes the death of infected cells. Similarly to B cells, some T cells form memory cells that allow the body’s immune system to respond efficiently if the same antigens make it past the innate system.

Immunology and Immunogenicity
Immunogenicity is the ability of a substance to elicit a response from the complex human immune system. Innate immunity, antibody formation, cell-mediated cytotoxicity, T cell activation, or really any aspect of the immune system can influence immunogenic responses. Anti-drug antibodies, i.e., the formation of antibodies and how they react with an administered drug, are of special importance to us when studying immunogenicity for large molecule drug development. Having a deep understanding of the immune system and of the progress that has been made in immunology supports the ability to discover the best way to assess antibodies against an introduced biological drug, understand the purpose of the immune response, and determine the best assay strategy to mitigate immunogenicity risks.

This post is just the first in a series where I will discuss immunology and immunogenicity and how these areas of study are evolving using innovative science. Subsequent posts will discuss the challenges in immunogenicity testing as it relates to the immune system and the complex impact immunogenicity has on biological drugs. You can also watch the webinar I recently recorded with Bioanalysis Zone, entitled “Recent Aspects and Challenges in the Assessment of Immunogenicity”, to learn more about these important topics.

Check back weekly to learn more about our immunogenicity expertise and how we can provide quality services to positively impact the development of new, much needed biotherapeutics.

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