New targeted monoclonal antibody (mAb) therapies are making good on the promises of precision medicine—until they inexplicably stop working. When that happens, clinicians turn to Melissa Snyder, PhD, of Mayo Medical Laboratories, for a better understanding of the problem. As Synder described in Wednesday’s morning short course, “Clinical and Laboratory Aspects of Monoclonal Antibody Therapeutics,” clinical laboratories like hers have responded to this need with laboratory-developed tests (LDTs) for therapeutic drug monitoring (TDM) of drug concentration and antibodies against therapeutic mAbs (anti-drug antibodies or ADAs). “Many of the reasons that we traditionally do TDM do not apply to mAbs,” Snyder said. Most TDM of mAb therapies is for loss of response to therapy in inflammatory bowel disease, not toxicity or compliance.
The rise of mAb therapeutics has also introduced new mechanisms of assay interference, noted Maria Alice Willrich, PhD. “There are some cases when it is important to differentiate between endogenous mAb and therapeutic mAb,” Willrich said, and plasma cell dyscrasias are one of these cases. Serum protein electrophoresis (SPEP) and immunoelectrophoresis (IEP) are gold standards in diagnosing and following treatment efficacy in patients with plasma cell dyscrasias, and they reliably detect monoclonal antibody populations.
The sticking point comes when a patient with a pathologic mAb receives a therapeutic mAb—how can the lab tell the difference? Willrich indicated that usually it’s not possible. The only small clue is that currently available mAb therapies are an IgG kappa subtype.
Willrich provided an overview of common patterns of interference and explained possible future interventions, including new research assays that use antibodies against the therapeutic mAb and monoclonal immunoglobulin rapid accurate mass measurement (See abstract A-444).
Laboratories like Snyder’s that peform LDTs for mAb drug concentration and ADAs continue to perform comparisons with other institutions, and most assays demonstrate robust correlation for quantitative drug concentrations, Snyder said. The heterogeneous nature of ADAs, however, leads to much more variability in qualitative ADA assays. Snyder indicated that some of this poor correlation is related to how laboratories establish their positive and negative cutoffs. The clinical relevance of low titer is still unknown and laboratories are handling it differently.
Snyder has also found that ADA assays are differentially susceptible to negative interference from circulating drug, further complicating the already complex interpretation confronting laboratories. Those that send out this testing need to be aware of the method and limitations of the laboratory performing their testing.
Snyder emphasized that clinicians directly use therapeutic mAb concentrations and ADA assay results in their management decisions. A lower than expected drug concentration is a reasonable indication that there may be an ADA mechanism at work, and follow-up testing for ADA may be warranted.
ADAs form immune complexes with the mAb drug and increase clearance rates from the circulation, thereby decreasing drug concentration (and efficacy). If ADA testing is negative, physicians may increase dosing and retest trough levels. Conversely, when ADA testing is positive, patients will be transitioned to one of the new medications available—which may not have an associated LDT for subsequent monitoring. If the trough sample has a high concentration of drug, Snyder’s lab does not recommend ADA testing, as it is unlikely that increased drug clearance via immune complexes is causing the lack of therapeutic response.
The rise of mAb therapies has enabled precision medicine to expand quickly, providing improved quality of life to patients worldwide. Simultaneously, new complications have arisen that require clinical laboratories’ diligence in providing necessary testing and knowing about new assay interferences to provide enhanced care to patients.