Therapeutic Monoclonal Antibody Drug Monitoring

Therapeutic monoclonal antibodies (mAbs) are laboratory-engineered antibodies. Unlike chemically synthesized therapeutics, therapeutic mAbs are produced in a living cellular system, although modern approaches include creating the genes needed in vitro. 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 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 that 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, including many that are 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 escalating dose 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 relate to one another. 

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 Rheumatology (ACR)¹ or the American Academy of Dermatology (AAD).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 that include both.

Measuring both drug and anti-drug antibody levels simultaneously may speed determination of bioavailability and the cause of treatment failure.

However, monitoring only drug levels is appropriate if a sequential approach is preferred. In addition, 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 recognizes the drug’s antigen binding site (called an anti-idiotypic antibody). The latter approach is more common. Anti-idiotypic antibodies capture the drug and then a second anti-idiotypic antibody with a label also binds the drug. Measuring the signal produced by the label allows the presence of the drug to be detected. Although enzymes were originally used as the label, many modern automated assays use a chemiluminescent label instead. Quest Diagnostics utilizes immunoassays for adalimumab, infliximab-dyyb (Inflectra^®), vedolizumab and ustekinumab.^9-13

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 is then measured.

Other methods include mass spectrometry and cellular assays that can demonstrate the ability of the drug to block the biological effect of the target.

Concentrations of therapeutic monoclonal antibody drugs and anti-drug antibodies can vary significantly 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