IVD Can Contribute to t-mAb Effectiveness

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By Rob Camp, PhD - Therapeutic monoclonal antibodies (t-mAbs) are useful tools in stemming disease if they can maintain their effectiveness. These treatments are used in treatments for autoimmune and inflammatory disorders (AIIDS) like rheumatoid arthritis, Crohn’s disease, and asthma, for a number of cancers, to prevent transplant rejections, and to target the amyloid-β plaques common in Alzheimer’s disease. These treatments use a variety of mechanisms, such as radioactive anti-lymphoma antibodies, malignancy-targeting antibodies that convert into cytotoxic drugs when bound to enzymes, or antibodies that are able to circumvent defenses that tumors use to suppress the immune response.Occasionally, t-mAbs lose their effect after a while, and clinicians need to figure out why; this was the subject of a talk presented recently at AACC by Drs. Melissa Snyder and Maria Alice Willrich of Mayo Medical Laboratories. Kalorama reports on some of the concepts detailed here.  Audio of their presentation is available at Mayo Labs Soundcloud site: https://soundcloud.com/mayocliniclabs/aacc-2017-maria-alice-willrich-phd-and-melissa-snyder-phd.

For more information on the market opportunity for companion testing, see Kalorama's report, The World Market for Companion Diagnostic Tests.

When mAb therapies fail, clinical labs often administer lab-developed tests (LDTs), such as serum protein electrophoresis and immunoelectrophoresis, for therapeutic drug monitoring (TDM) of drug concentration and anti-drug antibodies (ADAs), which reduce a drug’s efficacy by binding to the therapeutic mAbs, reducing the concentration of active drug in circulation. According to Willrich, the problem is, when making these observations, distinctions need to be made between pathological or endogenous mAbs, and those used in the treatment regimen; however, apart from knowing that all mAb therapies are derived from the same immunoglobulin subtypes (Gk), making such distinctions are nearly impossible. Labs that do perform LDTs will consult with one another and find that their quantitative analyses for drug concentration are consistent. Unfortunately, because of the specificity –and therefore heterogeneity – of ADAs, qualitative assays for their detection are highly variable, in part also because of how labs interpret assay results. Complicating matters further is that assays for ADA detection can suffer from interference by circulating t-mAb concentrations.

Because clinicians depend on these analyses and refer to them directly for managing patient treatment, knowing about these limitations is important, and solutions must be worked out. If initial testing shows that, despite the loss of therapeutic effect, drug concentrations are high enough, Snyder does not recommend ADA testing, as that there are more likely causes for a reduction in a drug’s efficacy. If ADAs are not detected in TDM, the patient will simply be given a stronger dose and monitored further; if they are, the patient will be given a different mAb therapy, which is not foolproof, as not all drugs have lab-prepared tests for treatment monitoring.

While the use of mAbs allow clinicians to more precisely target causes of illness and care better for their patients, these methods of therapy do have their challenges, and laboratories must be up to the task of recognizing the limitations of testing the efficacy of therapeutic mAbs, and working towards mitigating them. Willrich has discussed possible future interventions to help reduce interference, such as assays that use antibodies against t-mAbs as well as including the use of new methods of quantification more effective than the electrophoretic techniques commonly used for this application. One such method, monoclonal immunoglobulin Rapid Accurate Mass Measurement (miRAMM), measures molecular mass, which is a primary defining characteristic of monoclonality in an antibody (monoclonal antibodies have conserved amino acid sequences, and thus are consistent in mass). Continued research into more advanced qualitative assays like these will help patients continue to receive effective treatment for autoimmune disorders and cancers.