Serum Natalizumab and Anti-Natalizumab Antibody Concentrations May Be Useful in Patient Management (P1-3.002)

Abstract

<h3>Objective:</h3> Natalizumab (NTZ) and anti-natalizumab antibody concentrations in serum are used together to provide patient-specific pharmacokinetic and immunogenic assessment to aid in patient management. <h3>Background:</h3> NTZ is a monoclonal antibody directed against the a4-integrin subunit of a4b1 and a4b7 integrins. NTZ is used to treat relapsing and remitting forms of multiple sclerosis. Although a majority of patients on standard dosing (intravenous 300 mg, every 4 weeks) reach therapeutic drug concentrations, about 10% of patients will eventually fail NTZ therapy due to the development of anti-NTZ antibodies. <h3>Design/Methods:</h3> Serum measurements of NTZ and anti-NTZ antibody levels are performed by novel lab developed electro-chemiluminescent immunoassays. The natalizumab drug assay is validated to measure free drug (pharmacodynamically active) level in serum. The anti-natalizumab antibody assay is quantitative and drug-tolerant, meaning that circulating drug in patient serum does not interfere with anti-NTZ detection and quantitation. <h3>Results:</h3> Here, we report concomitant measurement of NTZ and anti-NTZ antibody in 160 patient serum samples. Positive anti-NTZ levels from 24 to 235 ng/mL were found in 7.5% (12/160) patients. Anti-NTZ-free samples (148/160) had NTZ drug levels ranging from undetectable (&lt;1.0) to 85 ug/mL. The mean and median drug level in 90 samples (results &gt;1.0) was 10.8 and 2.7, respectively. 61/90 samples had therapeutic drug concentrations (at least 2.0 ug/mL). In the presence of anti-NTZ, 67% (8/12) had undetectable drug level and (4/12) had mean and median drug levels of 1.2 and 1.3, respectively, which is 9- or 2-fold lower than the mean and median drug levels of the anti-NTZ Ab -free group. <h3>Conclusions:</h3> Low serum NTZ and high anti-NTZ are associated with loss of clinical efficacy, while elevated NTZ may increase progressive multifocal leukoencephalopathy risk. Assays to measure biologic drugs and their anti-drug antibodies in patient serum may be useful tools in dose optimization and patient management. <b>Disclosure:</b> Dr. Yang has received personal compensation for serving as an employee of Labcorp. Dr. Chun has nothing to disclose.