Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies

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• 作者：Vipul Yadav^a ; Felipe Varum^b ; Roberto Bravo^b ; Esther Furrer^b ; Abdul W. Basit^a ; ^{a.basit@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Infliximab ; Adalimumab ; Monoclonal antibodies ; Oral delivery ; Gastrointestinal stability ; Tumor necrosis factor alpha (TNF-α)
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：11 April 2016
• 年：2016
• 卷：502
• 期：1-2
• 页码：181-187
• 全文大小：1026 K

文摘

Monoclonal antibodies (mAbs) are highly effective therapeutic agents, administered exclusively by the parenteral route owing to their previously-documented instability in the gastrointestinal (GI) tract when delivered orally. To investigate the extent of the validity of this assumption, the stability of the tumor necrosis factor alpha (TNF-α) neutralizing IgG1 mAbs, infliximab and adalimumab, was studied in human GI conditions. In gastric fluid, infliximab and adalimumab degraded rapidly, with complete degradation occurring within 1 min. In small intestinal fluid, the molecules were shown to be more stable, but nonetheless degraded within a short time frame of 30 min. Investigations into the mechanisms responsible for infliximab and adalimumab instability in the small intestine revealed that the proteolytic enzyme elastase, and to a lesser extent the enzymes trypsin and chymotrypsin, was responsible for their degradation. By contrast, in the human colon, 75% and 50% of the dose of infliximab and adalimumab, respectively, were intact after 60 min, with conversion of mAbs into F(ab’)2 Fab and Fc fragments detected in colonic conditions. These data indicate that therapeutic IgG1 antibodies are more stable in the colon than in the upper GI tract, therefore highlighting the potential for oral delivery of anti-TNF-α mAbs targeted to the colon.