Therapeutic Monoclonal Antibody Drug Monitoring

Antibodies are produced by cells called plasma cells, derived from B lymphocytes, in response to the presence of a foreign antigen. Usually, many different B lymphocytes respond to different parts of the antigen molecule and the response is called polyclonal. When all of the antibody is identical (derived from one B lymphocyte clone and directed against one antigenic determinant), it is called a monoclonal antibody.

Monoclonal antibodies intended to be used as therapeutic drugs were originally developed by fusing B lymphocytes from immunized animals (usually mice) with plasma cell tumors. Although they are now manufactured in different ways as well, they still fall into the general category of biologic drugs. They can be used to treat rheumatic diseases including inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, and many other diseases.^1-3

Treatment failure rates can vary depending on the drug and clinical indication. Up to one-third of patients experience primary treatment failure (no response to induction therapy).⁴ Up to about 50% of patients who initially respond to induction therapy with either infliximab or adalimumab later lose the effect and experience disease flares during ongoing maintenance therapy (secondary failure).^5,6

Several factors can lead to primary and secondary treatment failure. In patients with primary failure, subtherapeutic levels may indicate poor adherence, increased drug clearance, or other pharmacokinetic issues.

In patients with secondary failure, patients who respond to the drug initially (ie, during induction) experience subtherapeutic drug levels due to the development of anti-drug antibodies; that is, antibodies that target the therapeutic monoclonal antibody and decrease bioavailability. Newer monoclonal antibody drugs have been “humanized” to remove as much of the mouse part of the immunoglobulin as possible, or even made completely human. This has helped to reduce the production of anti-drug antibodies.

Although empiric treatment changes can be used to manage treatment failure, a testing-based strategy (ie, testing drug levels and/or anti-drug antibody levels) can help healthcare providers determine the mechanism of failure and better manage these patients.⁷ Testing-based strategies help characterize the mechanism of treatment failure as being pharmacodynamic (eg, presence of drug but lack of effect) or pharmacokinetic (eg, low bioavailability of drug due to metabolism issues or anti-drug antibodies). This information may help decide how to address failure, which may include dose escalation or switching to a different biologic or drug class.

Table 1 provides a general interpretation of how therapeutic monoclonal antibody drug levels and anti-drug antibody levels mean in relation to one another. 

Yes. The 2017 American Gastroenterological Association (AGA) guidelines recommend reactive monitoring (ie, in response to suboptimal disease control) of trough drug levels to guide treatment changes in patients receiving biologics for management of active inflammatory bowel disease.³ Recommendations for drug level testing are not specified in guidelines from the American College of Rheumatology¹ or the American Academy of Dermatology.²

Measuring both drug and anti-drug antibody levels at the same time may speed determination of bioavailability and the cause of treatment failure. Measuring only drug levels is appropriate if a sequential approach is preferred. Measuring only anti-drug antibody levels may be appropriate if insufficient bioavailability has been established. 

Table 2 outlines the Quest Diagnostics tests available for therapeutic monoclonal antibody drug monitoring. Tests for drug and anti-drug antibody levels are available individually and as profiles.

No. The two major approaches are immunoassay and homogeneous mobility shift assay (HMSA). Immunoassays use antibodies that recognize the antigen binding site of the therapeutic monoclonal antibody. One captures the drug and the other contains a label which allows the resulting complex to be measured. Such assays are called “bridging” immunoassays. Although enzymes were originally used as the label, many modern automated assays use a chemiluminescent label instead. In HMSA, the target of the therapeutic monoclonal antibody is labeled and allowed to bind to any drug present. The change in size of the labeled target due to this binding to the drug can be measured.

Other methods include mass spectrometry and cellular assays which can demonstrate the ability of the drug to block the biological effect of the target. Quest Diagnostics utilizes immunoassays for adalimumab, infliximab [and Inflectra^® (infliximab-dyyb)], vedolizumab and ustekinumab.^9-13 Concentrations of therapeutic monoclonal antibody drugs and anti-drug antibodies can show significant variability between methods. Therefore, whenever possible, the same assay should be used when monitoring a given patient.⁷

All Quest immunoassays for vedolizumab and ustekinumab are validated for both the biologic drug and any FDA-approved biosimilars. Quest infliximab assays are only validated for Inflectra^® (infliximab-dyyb).

The American College of Rheumatology (ACR),¹ the American Gastroenterological Association (AGA),³ and the FDA¹³ all advocate applying FDA-approved biologic clinical guidance to the use of the respective FDA-approved biosimilar.¹⁴