Original ResearchFull Report: Basic and Translational—Alimentary TractInfliximab–Tumor Necrosis Factor Complexes Elicit Formation of Anti-Drug Antibodies
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Section snippets
Mice
Female C57BL/6 mice (6–8 weeks, 17–20 g) were obtained from Harlen (Rehovot, Israel) and acclimatized for ≥1 week before experimentation. Mice were fed a standard pellet diet and provided with tap water ad libitum. Blood was drawn at baseline and used as a matching control for each mouse. Mice were injected with infliximab by the intraperitoneal (IP) route (followed by intravenous [IV] injection of hTNF in some experiments) at the indicated concentrations (note pharmacokinetics of IP vs IV
Effect of Infliximab Concentration on Immunogenicity
Four to 5 mice in each dosing group were injected with infliximab at baseline, and blood was drawn at regular intervals.
Discussion
Our results suggest that local intestinal immune activation by infliximab-TNF complexes, differentially formed under different drug/target ratios, instigates intestinal production of ADA in an Fc-independent manner. This process involves endocytosis and more effective infliximab-TNF complex uptake compared with infliximab only by antigen-presenting cells, which thereafter secrete proinflammatory cytokines.
ADA production during the time course of infliximab treatment occurs in approximately 50%
Acknowledgments
Author contributions: Guarantor of article: Haggai Bar-Yoseph. Specific author contributions: Haggai Bar-Yoseph, Sigal Pressman, Alexandra Blatt, Shiran Gerassy, and Naama Maimon performed the study. Haggai Bar-Yoseph, Sigal Pressman, Shomron Ben-Horin, and Yehuda Chowers conceived the study. Haggai Bar-Yoseph, Sigal Pressman, and Yehuda Chowers wrote the paper. Haggai Bar-Yoseph, Sigal Pressman, Alexandra Blatt, Shiran Gerassy, Naama Maimon, Elina Starosvetsky, Bella Ungar, Shomron Ben-Horin,
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Conflicts of interest These authors disclose the following: Shomron Ben-Horin received consulting and advisory board fees and/or research support from AbbVie, MSD, Janssen, Takeda, Pfizer, GSK, and CellTrion. Yehuda Chowers received consulting fees from AbbVie, Janssen, Takeda, Pfizer, Eli Lilli, Medtronics, Neopharm, Protalix; speaker fees from AbbVie, Janssen, and Takeda; and grants from AbbVie and Takeda. Bella Ungar has received consultation/lecture fees from Takeda, AbbVie, Jannsen, and Neopharm. The remaining authors disclose no conflicts.
Funding This study was supported by a generous grant from the Leona M. and Harry B. Helmsley Charitable Trust.
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Authors share co-first authorship.