P058 Serum infliximab and corresponding anti-infliximab antibody: Analysis of over 30,000 patient results using lab developed chemiluminescent immunoassays

Abstract

BACKGROUND: Assays to measure TNF inhibitors and anti-drug antibodies (ADAb) in patient serum are being utilized to manage failure to respond and loss of response. These monitoring assays may also be used to proactively titrate doses and dosing intervals (1). Here, 37,165 infliximab (IFX) patient results over 4 years were analyzed. METHODS: Measurements of drug and ADAb levels were performed by lab developed chemiluminescent immunoassays (2). The lower limits of quantitation are 0.4 μg/mL for IFX and 22 ng/mL for its ADAb. Drug assays measure free (ADAb-unbound) drug while ADAb assays detect total antibodies (including IgM and IgG subtypes) and are drug- tolerant to the presence of up to >50 μg/mL of drug. Clinical histories and blood collection timing are unknown. RESULTS: Of 37,165 measured IFX samples, 55% (20,359) were ADAb-free and 45% (16,806) had measurable anti-infliximab antibodies, ranging in concentration from 22 to 3.5 million ng/mL. In the absence of ADAb, IFX concentrations were from 0.4 to >50 μg/mL, with the majority (>60%) between 3.0 to 20 μg/mL. In the presence of ADAb, an inverse relationship between IFX concentrations and anti-IFX antibodies was demonstrated. As a baseline reference, an ADAb-free mean drug level from 16,463 samples with IFX between 0.4 and 30 μg/mL was found to be 10.0 μg/mL. Mean IFX concentrations decreased in samples with increasing ADAb. Low ADAb (<200 ng/mL) appears to have minimal impact on mean drug levels while high ADAb (>1,000 ng/mL) is invariably associated with severely diminished IFX (10% or less than the mean). CONCLUSION(S): Upon analysis of 37,165 infliximab patient samples, 45% exhibited anti-infliximab antibodies. Though collection timing and clinical histories are not known, we found that of all ADAb- free samples, about one third (36%) were within the target range of 3–10 μg/mL for infliximab and 36% of samples were subtherapeutic at <3.0 μg/mL. High titer ADAb are almost invariably associated with very low or absent IFX levels. In contrast, low titer antibodies have little or no impact on drug levels. Our findings are consistent with American Gastroenterological Association Critical Care Pathways for Crohn's Disease and Ulcerative Colitis where low and high antibody scenarios are managed very differently (increase drug dose/consider immunomodulatory vs switch within class). It may be possible to treat away low titer ADAb by increasing drug or adding an immunomodulator (3). Therefore, drug-tolerant anti-drug antibody assays that have been designed both (1) to detect low level ADAb and (2) to distinguish low to intermediate to high titers with high resolution (from 22 to 2,000+ ng/mL) may be most helpful in preventing, managing and treating immunogenicity.