Immunogenicity describes the ability of a substance to provoke a response from the immune system. Any substance with this property is considered an immunogen, and it is linked to antigenicity—the capacity of a molecule, or antigen, to bind with products of an immune response like antibodies. While related, the two terms are distinct.
A substance can be antigenic, meaning it can bind to immune receptors, without being immunogenic, which means initiating a full immune reaction. For a substance to be immunogenic, it must first be antigenic, but the reverse is not always true. This distinction is important for understanding how the body responds to different substances.
The Immune Response Mechanism
An immune response begins when antigen-presenting cells (APCs), such as macrophages and dendritic cells, encounter a foreign substance. The APC engulfs the substance, breaks it into antigenic fragments, and displays them on its surface using major histocompatibility complex (MHC) proteins. This display of the antigen initiates the adaptive immune response.
Once an APC presents an antigen, it travels to a lymph node to interact with other immune cells. Helper T-cells, a type of lymphocyte, have receptors that recognize and bind to the specific antigen-MHC combination on the APC. This binding activates the helper T-cell, causing it to multiply and release chemical signals that coordinate the immune defense.
These signals stimulate B-cells, another type of lymphocyte. Upon activation by a helper T-cell, B-cells begin to clone themselves. Some clones differentiate into plasma cells, which produce millions of antibodies that are released into the bloodstream to find and neutralize the foreign substance. The remaining B-cells become long-lived memory cells that retain the antigen’s “memory,” allowing for a faster response upon future exposure.
Desired vs. Undesired Immunogenicity
The context of an immune reaction determines if it is beneficial or detrimental. In some situations, a strong immune response is the goal. This is the principle behind vaccination, where provoking immunogenicity is the primary objective. A vaccine introduces a harmless version or component of a pathogen, prompting the immune system to mount a defense without causing illness.
The immunogenic components in a vaccine trigger the activation of T-cells and B-cells, leading to the production of antibodies and the formation of memory cells. These memory cells provide long-term protection, enabling the body to quickly recognize and neutralize the actual pathogen if encountered in the future. A vaccine’s effectiveness is related to its ability to induce a durable immune memory, making high immunogenicity a sought-after characteristic in vaccine design.
Conversely, immunogenicity can be an unwanted complication with therapeutic proteins. These complex biologic drugs, such as monoclonal antibodies used to treat autoimmune diseases or cancer, are large and can be recognized as foreign. Because of this, they have the potential to provoke an immune response.
When the body reacts against a therapeutic protein, it produces anti-drug antibodies (ADAs). These ADAs can have several negative consequences. They can bind to the drug and neutralize its activity, render the treatment ineffective, accelerate the drug’s clearance from the body, or trigger adverse effects, including allergic reactions. This unwanted immunogenicity poses a challenge in drug development and patient management.
Factors Influencing the Immune Reaction
The intensity of an immune response is influenced by factors related to the substance itself, the patient, and how it is administered. The characteristics of the immunogenic substance play a large part. Larger and more chemically complex molecules are more likely to provoke a response than smaller, simpler ones. The origin of a substance also matters; a protein from a non-human source is more likely to be recognized as foreign than one that is structurally similar to human proteins.
Individual patient characteristics are another factor. A person’s genetic makeup, particularly the genes that code for MHC proteins, can determine how strongly their immune system reacts to a specific substance. Age and overall health status also affect immune function, as the very young, elderly, or those with compromised immune systems may respond differently. The underlying disease being treated can also be a factor in the likelihood of developing an immune reaction.
The way a substance is administered can modulate the immune response. The dosage, frequency of administration, and the route all have an impact. For instance, an injection into a vein might result in a different immune reaction compared to an injection under the skin. Repeated or long-term administration of a therapeutic protein can also increase the likelihood of the immune system mounting a response.
Assessing Immunogenicity
Assessing immunogenicity is a standard part of developing vaccines and therapeutic drugs to ensure their safety and effectiveness. Scientists use a multi-stage approach to predict and measure potential immune responses long before a product reaches patients. This process helps identify and mitigate risks early in development.
The evaluation begins with computational, or in silico, methods. These computer-based tools use algorithms to analyze the amino acid sequence of a protein therapeutic and predict which portions are likely to bind to MHC molecules and be presented to T-cells. This flags it as a potential immunogen and allows researchers to redesign or select drug candidates with a lower predicted risk of causing an immune reaction.
Following computational screening, laboratory assays are performed. These in vitro tests can involve exposing human blood cells to the drug in a controlled environment to see if T-cells are activated. The final stage of assessment occurs during human clinical trials. Throughout these trials, blood samples from participants are regularly collected and analyzed for the presence of anti-drug antibodies (ADAs). This monitoring provides real-world data on the incidence and clinical impact of any unwanted immune responses.