As infliximab was one of the first therapeutic monoclonal antibodies on the market to treat inflammatory bowel disease and as treatment alternatives were limited, many data exist on how to optimize the treatment with infliximab. Since a drug can only exert its function when adequate concentrations are achieved in the serum, it was soon discovered that the concentrations of infliximab just before the next dose administration (i.e. trough concentrations) can be linked to clinical response. Patients with low trough concentrations are more prone to relapse and can benefit from a dose intensified therapy regimen. In the laboratory for Therapeutic and Diagnostic Antibodies, enzyme-linked immunosorbent assays to determine the concentration of infliximab have been developed and recently optimized using specific, monoclonal anti-infliximab antibodies to detect infliximab. In addition, our lab aims to develop rapid point-of-care assays for the detection of infliximab allowing immediate dose optimization when a patient visits the hospital/infusion center. Besides infliximab monitoring, it is equally important to assess whether a patient develops an immune response against infliximab, i.e. anti-infliximab antibodies, which neutralize the activity of infliximab and accelerate its clearance leading to loss of response to treatment. Hereto, several assays to determine anti-infliximab antibodies have been developed, ranging from drug-sensitive to drug-tolerant immunoassays. Both the infliximab concentration and anti-infliximab antibody concentration can be used as objective tools in clinical decision making and allow generating treatment algorithms for patients with inflammatory bowel disease.

Golimumab is the most recently marketed anti-tumor necrosis factor-alpha (anti-TNF) biological available to treat patients with moderate-to-severe ulcerative colitis (UC). The pivotal PURSUIT-SC induction study showed that 51.0% of the patients in the golimumab 200/100 mg group responded clinically upon induction therapy. The PURSUIT-maintenance study showed that in 47.0% of the induction-responders, clinical response to 50 mg golimumab every four weeks was maintained through week 54. Question posed is whether adequate dosing of and exposure to golimumab could form a basis for clinical effectiveness of golimumab therapy. As previously reported for both infliximab and adalimumab, it can be hypothesized that also golimumab evokes an immune response resulting in the formation of anti-drug antibodies that may or may not be neutralizing and that may or may not be persistent. To date, little is known about anti-golimumab antibody development and its relation to clinical response in patients with UC. In addition, many questions concerning immunogenicity have not yet been answered and different methods of detection are being used, which makes the results difficult to compare. In the laboratory for Therapeutic and Diagnostic Antibodies, monoclonal-antibody based enzyme-linked immunosorbent assays were developed to determine golimumab and anti-golimumab concentrations in a cohort of patients with UC that started golimumab therapy.

Therapeutic drug monitoring is an emerging strategy to optimize biologic treatment of chronic inflammatory disease. Adalimumab serum concentrations correlate positively with clinical remission and mucosal healing. Despite its fully human character, adalimumab can elicit an immune response in patients. Therefore, in patients who have undetectable or low adalimumab concentrations, it is recommended to determine the anti-adalimumab antibody concentration. In the laboratory for Therapeutic and Diagnostic Antibodies, a panel of highly specific antibodies towards adalimumab was generated, which enabled us to carefully select an antibody (pair) for use in different ELISA types for the determination of adalimumab and anti-adalimumab antibody concentrations in serum. The two novel adalimumab ELISAs can be used interchangeably and have excellent agreement with two commercially available ELISAs developed by Sanquin and apDia, which will facilitate implementation of universalized treatment algorithms.

TNF-alpha inhibitors are effective for inducing and maintaining response and remission in patients with ulcerative colitis and Crohn’s disease. The therapeutic response of individual patients is difficult to predict due to the high risk of primary nonresponse (30%) and secondary loss of response after an initial successful therapy (up to 50% within the first year). Reasons for nonresponse are not completely understood and presumably multifactorial. It has been shown that poor therapeutic outcome correlates with low drug exposure, reflecting in low trough concentrations (i.e., the drug’s serum concentration just before the next administration of the drug). Population pharmacokinetic-pharmacodynamic (PK-PD) modeling is a valuable tool to gain insight in the variability in drug exposure and response. PK-PD modeling also allows identification of patient descriptors (demographics, genetics, biochemistry, etc.) that explain this variable drug exposure and response. For example, it has already been shown that high C-reactive protein, low albumin, presence of anti-drug antibodies, etc. predict a more rapid clearance of the drug. Male gender and higher body weight predict a higher volume of distribution. This type of information supports the development of personalized, adaptive dosing of anti-TNF biologicals based on these patient descriptors, in order to obtain adequate drug exposure and subsequently a good therapeutic response. The Laboratory for Therapeutic and Diagnostic Antibodies is experienced in population PK-PD modeling and simulation and aims to develop and clinically validate personalized dosing algorithms that allow better allocation of the resources in order to obtain a higher (cost) efficacy.

Ustekinumab is a fully human IgG1K monoclonal antibody that inhibits IL-12 and IL-23 through their common p40 subunit and is approved for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adults. It has recently completed two phase II clinical trials in patients with active Crohn’s disease and is currently undergoing three phase III clinical trials. Preliminary results of the phase III UNITI-2 study showed positive clinical response and remission in patients with moderate to severe Crohn’s disease. Studies on the immunogenicity of ustekinumab and the clinical relevance of measuring trough levels and anti-drug antibodies in patients with inflammatory bowel disease are currently lacking. However, in psoriasis patients treated with ustekinumab almost half of the patients needed dose-intensification, suggesting the role of anti-drug antibody formation against ustekinumab. The production of neutralizing anti-drug antibodies can accelerate drug clearance, leading to decreased serum levels and, ultimately, to treatment failure. The Laboratory of Therapeutic and Diagnostic Antibodies will therefore develop enzyme-linked immunosorbent assays to determine ustekinumab serum concentrations and anti-ustekinumab antibodies using highly specific monoclonal antibodies. These assays will allow clinicians to incorporate therapeutic drug monitoring into the clinical practice to optimize treatment with ustekinumab by maintaining effective drug concentrations over time.

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