SOUTH SAN FRANCISCO, Calif.—Clinical-stage biopharmaceutical company Applied Molecular Transport (AMT) had research accepted for publication in the November 2020 online edition of The Journal of Immunology, the company announced last week. The article, “A Novel Fusion of Interleukin-10 Engineered to Traffic Across Intestinal Epithelium to Treat Colitis,” detailed AMT-101's mechanism of action as well as preclinical data supporting its potential as a treatment for ulcerative colitis and other inflammatory diseases.
According to AMT, its proprietary technology platform “exploits existing natural cellular trafficking pathways to actively transport therapeutics through the intestinal barrier directly into the underlying immune-rich milieu of the lamina propria.”
AMT-101 is a gastrointestinal-selective, oral fusion of hIL-10 and its proprietary carrier molecule, which AMT is advancing in four Phase 2 clinical trials in inflammatory bowel diseases and rheumatoid arthritis. The compound is designed to cross the intestinal epithelium (IE) barrier with limited entry into the bloodstream, thereby focusing hIL-10 in the lamina propria of the gastrointestinal (GI) tissue and ideally avoiding the side effects observed with systemic administration.
“Our breakthrough platform technology enables the active transport of oral biologics by solving the long-standing industry challenge of transporting large, biologically-active molecules efficiently across the intestinal barrier,” said Dr. Randall Mrsny, chief scientific officer and co-founder of AMT. “Our technology platform is based on native, active vesicular transcytosis mechanisms to rapidly and efficiently traverse intestinal epithelial cells. Once across this epithelia barrier and in the underlying intestinal lamina propria, AMT-101 targets local macrophages and lymphocytes to activate cell signaling pathways, inducing tissue and circulating markers demonstrating IL-10 mechanism of action through cognate receptor engagement and down-stream signaling. Importantly, we continue to leverage our technology platform to be a robust engine for the design and development of a wide range of oral biologic therapeutics.”
In-vitro and in-vivo characterization of AMT-101 has demonstrated its ability to efficiently cross the human intestinal epithelium by an active, receptor-mediated vesicular transcytosis process, activating IL-10 receptor signaling to increase cellular phospho-STAT3 (pSTAT3) levels in macrophage cells. In models of induced colitis, AMT-101 was able to correct pathologic changes by suppressing pro-inflammatory markers of disease and induce anti-inflammatory cytokines in both the intestinal tissue and in plasma.
“Our preclinical data has also shown that oral hIL-10 can be targeted to the intestinal lamina propria with minimal systemic PK, suggesting that we may be able treat IBD patients with fewer toxicities than previously observed following the systemic administration of this potent cytokine,” explained Dr. Tahir Mahmood, CEO and co-founder of AMT. “We have evaluated AMT-101 in active ulcerative colitis patients in a Phase 1b study and demonstrated reductions in objective clinical measures of intestinal inflammation such as fecal calprotectin and histopathologic scores, as well as systemic indicators of inflammation such as C-reactive protein, after just 14 days of treatment. We are excited about our ongoing and planned Phase 2 trials for AMT-101 in IBD and rheumatoid arthritis, and will continue to leverage the platform to build our pipeline of differentiated oral biologic therapeutics.”
SOURCE: Applied Molecular Transport press release
