TY - JOUR
T1 - Anti-infliximab Antibodies with Neutralizing Capacity in Patients with Inflammatory Bowel Disease
T2 - Distinct Clinical Implications Revealed by a Novel Assay
AU - Weisshof, Roni
AU - Ungar, Bella
AU - Blatt, Alexandra
AU - Dahan, Aviva
AU - Pressman, Sigal
AU - Waterman, Matti
AU - Kopylov, Uri
AU - Ben-Horin, Shomron
AU - Chowers, Yehuda
N1 - Publisher Copyright:
© Copyright 2016 Crohn's & Colitis Foundation of America, Inc.
PY - 2016/6/7
Y1 - 2016/6/7
N2 - Background: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. Methods: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. Results: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 g/mL, respectively P 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P 0.028). Conclusions: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease.
AB - Background: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. Methods: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. Results: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 g/mL, respectively P 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P 0.028). Conclusions: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease.
KW - antidrug antibody
KW - inflammatory bowel disease
KW - infliximab
KW - loss of response
UR - http://www.scopus.com/inward/record.url?scp=84976337418&partnerID=8YFLogxK
U2 - 10.1097/MIB.0000000000000797
DO - 10.1097/MIB.0000000000000797
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C2 - 27120567
AN - SCOPUS:84976337418
SN - 1078-0998
VL - 22
SP - 1655
EP - 1661
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
IS - 7
ER -