Antibodies: The Hidden 20% of the Plasma Proteome

Antibodies are best known for defending the body against pathogens, but they also represent a large and underexplored component of the plasma proteome. By capturing antibody specificities, antibody profiling reveals how the immune system responds to abnormal molecular changes, information that cannot be captured by protein abundance measurements alone.

The remarkable diversity of antibodies

A healthy adult has an estimated 10 million distinct antibody sequences circulating in plasma¹. These molecules are exquisitely tuned to recognize specific proteins or molecules – called antigens – through their unique shape and chemical complementarity. This incredible diversity is how the immune system tracks and responds to an enormous range of biological states, such as infection, injury, inflammation and even cancer.

Autoantibodies as early disease biomarkers

In some diseases, the immune system flags the body’s own proteins as threats, producing autoantibodies². These immune responses can emerge months or even years before clinical symptoms, making them powerful tools for early detection^3-6.

For example, in Type 1 diabetes, autoantibodies targeting insulin-producing pancreatic beta cells can be detected months or even years before diagnosis⁷. This pre-symptomatic window creates opportunities for earlier intervention and improved outcomes.

Why autoantibodies reflect pathology

Importantly, autoantibodies are not produced at random^2,6,8,9. They often arise through a limited set of biological mechanisms that are closely linked to pathological processes, rather than normal healthy states. Autoantibody production is triggered when self-proteins change in ways that trigger immune recognition, such as:

• Rapid or abnormal changes in protein abundance
• Genetic mutations or abnormal RNA processing
• Proteins appearing outside their normal cellular location
• Aberrant post-translational modifications
• Protein misfolding or aggregation
• Abnormal proteolytic activity

Because these events are tightly linked to pathology, the antibodies generated against them are often highly disease relevant.

Why are antibodies important biomarkers?

Antibodies are uniquely powerful biomarkers because they are:

• Specific: Reflect immune recognition of abnormal proteins
• Early: Appear before symptoms
• Stable: Persist over time
• Predictive: Correlate with disease risk and outcomes
• Accessible: Measurable in peripheral blood
• System-wide: Capture signals across tissues

By profiling antibodies, researchers gain insight into which molecular changes the immune system flags as biologically meaningful¹⁰. This immune-informed perspective enhances disease detection and risk prediction, while highlighting immunogenic protein targets that may be biologically relevant for therapeutic research (Vincent, Gout, Shi, Runbeck, Patel).

Why “hidden”?

Antibodies (or immunoglobulins) make up about 20% of the plasma proteome, yet they’re often overlooked in proteomics studies (Figure 1)¹¹. That’s because mass spectrometry – one of the most widely used tools in proteomics – cannot measure antibody specificity at high throughput^12,13. In other words, it can tell you how much antibody is present, but not what it’s binding to.

That’s a missed opportunity.

Protein microarrays address this gap by enabling high-throughput analysis of antibody specificity. For instance, the KREX™ i-Ome™ Discovery platform profiles antibody binding against thousands of full-length, correctly folded human proteins.

Why antibody profiling complements protein profiling

Antibody and protein profiling offer two perspectives on the same biological story:

Combining both approaches enables deeper biomarker discovery, stronger target validation and a more complete understanding of disease biology.

Why antibody profiling matters

Incorporating antibody profiling into plasma proteomics research provides a richer, more complete view of health and disease by revealing biologically significant and immunologically relevant protein antigens. Beyond detection, this immune-centric perspective can inform drug and vaccine development by identifying biomarkers associated with protection or pathology, and by revealing early indicators of efficacy or safety^14-19.