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AMT-101: an oral human IL-10 fusion protein

Presented by
Dr R. Mrsny, Applied Molecular Transport, USA
ECCO 2020
A newly designed chimaera of human IL-10 genetically fused to a non-toxic and poorly immunogenic fragment of the cholix exotoxin, termed AMT-101, demonstrated efficacy in preclinical models of colitis and has advanced to the clinic. Its gastro-intestinal selectivity should lead to improved safety.

IL-10 is a central anti-inflammatory cytokine that can modulate many pro-inflammatory signals, but clinical application has been limited by dose-limiting systemic side effects. This led to the development of a new chimaera of human IL-10 termed AMT-101.

In mice, the oral gavage of AMT-101 blocked histological changes of colonic tissue associated with oxazolone-induced colitis [1]. AMT-101 curbed increases in serum levels of pro-inflammatory cytokines IL-1β, IL-6, and IL-17A, as well as IL-10 (see Figure). Cynomolgus monkeys dosed orally with AMT-101 showed much lower serum levels than after intravenous injection of AMT-101 [1]. First author Dr Randall Mrsny (Applied Molecular Transport, San Francisco, USA) said these studies provide strong evidence that AMT-101 can effectively reach the intestinal lamina propria to deliver biologically active IL-10 following transcytosis across the intestinal epithelium. The gut-selective nature of the responses suggests AMT-101 may avoid the systemic toxicity of IL-10.

Figure. Serum levels of IL-1β, IL-6, IL-17A, and IL-10 in naïve and in vehicle- and AMT-101-treated mice [1]

Dr Mrsny proposed that AMT-101 has potential as stand-alone as well as combination therapy. A phase 1a study of AMT-101 in healthy subjects has been completed; it is currently being evaluated in a phase 1b trial in patients with active ulcerative colitis. Dr Mrsny stressed that the use of AMT-101 needs not be limited to delivering IL-10: “It is capable of carrying any biological currently in the clinic”.

      1. Mrsny R, et al. ECCO-IBD 2020, OP39.

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