Therapeutic Monoclonal Antibody Drug Monitoring

Therapeutic monoclonal antibodies (mAbs) are laboratory engineered proteins that mimic natural antibodies produced by the human immune system. Unlike chemically synthesized therapeutics, therapeutic mAbs are produced in a living cellular system. Their high specificity can reduce many off-target side effects, but they carry their own distinct risks, including serious infections and infusion reactions. Therapeutic monoclonal antibodies may be used to treat inflammatory bowel disease, systemic rheumatic disorders such as rheumatoid arthritis, psoriasis, and many other diseases.^1-3

Treatment failure rates can vary depending on the drug and clinical indication. Some patients experience primary treatment failure (no response to induction therapy).⁴ Other patients respond initially to induction therapy but later lose their response and experience disease flares during ongoing maintenance therapy (secondary failure).^5,6

In patients with primary failure, causes include poor adherence or increased drug clearance. In patients with secondary failure, the major cause is the development of anti-drug antibodies which target the therapeutic monoclonal antibody and lower bioavailability. Newer monoclonal antibody drugs have been “humanized” to remove as much of the mouse part of the immunoglobulin as possible. Many are 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

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 which include both.

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. 

No. The 2 major approaches are immunoassay and homogeneous mobility shift assay (HMSA). Immunoassays use either the target of the therapeutic monoclonal antibody or an antibody that recognize the drug’s antigen binding site. These capture the drug and then a labeled antibody to the drug binds to this complex. This allows the resulting complex to be measured. 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-dyyb (Inflectra^®), 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 infliximab-dyyb (Inflectra^®) 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