P066 The relationship between serum adalimumab and corresponding anti-adalimumab antibody levels: analysis of over 20,000 patient results

Abstract

BACKGROUND: Adalimumab (ADL) is a TNF inhibitor administered by injection. Serum assays of ADL and its anti-drug antibodies (ADAb) are 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, 22,012 adalimumab (ADL) patient results were analyzed. METHODS: Measurements of drug and ADAb levels were performed by lab developed chemiluminescent immunoassays (2). The lower limits of quantitation are 0.6 μg/mL for adalimumab and 25 ng/mL for anti-adalimumab antibodies. 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 >20 μg/mL of drug. Clinical histories and blood collection timing are unknown. RESULTS: Of 22,012 measured adalimumab samples, 60% (13,176) were ADAb-free and 40% (8,836) had measurable anti-adalimumab antibodies. Of all ADAb-free samples, the majority (10,171 or 77%) had ADL concentrations between 3 and 30 μg/mL while drug levels were <3 μg/mL in 2,495 (19%). Of ADAb-positive samples, most were positive in the low to intermediate titer range (25 to 200 ng/mL) Furthermore, as ADAb increase, their corresponding mean drug concentrations diminish. Low concentrations of ADAb (<100 ng/mL) appear to have minimal impact on mean drug levels where the baseline mean adalimumab (6.1 μg/mL) was calculated from 11,085 ADAb-free samples with adalimumab from 0.6 to 15 μg/mL. ADAb titers between 100 and 300 ng/mL are associated with a moderately diminished mean adalimumab (3.4–5.6 μg/mL) while high ADAb titers (>300 ng/mL) are invariably associated with diminished free ADL concentrations <30% of the mean. CONCLUSION(S): Of 22,012 samples, 60% were ADAb-free. Of those, about one third (37%) were within the target range of 5–10 μg/mL for adalimumab while 36% of samples were subtherapeutic at <5.0 μg/mL. Anti-adalimumab antibodies occurred in 40% of samples, and ADL drug concentrations were inversely related to anti-adalimumab antibody titers where low titer ADAb may have little or no impact on free drug levels while high titer ADAbs are associated with very diminished or absent drug. These 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. 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 25 to 2,000+ ng/mL) may be most helpful in preventing, managing and treating immunogenicity.