Discovery of a therapeutic antibody for the treatment of inflammatory bowel disease and type I diabetes

Preventing apoptopic cell loss in IBD and insulin-dependent diabetes patients
Insulin-like growth factor binding-protein 3 (IGFBP3) binds to Transmembrane Receptor 219 (TMEM219) on intestinal stem cells (ISCs) and pancreatic beta cells and mediates cell death/apoptosis in an IGF1-independent way. Dysregulation of the IGFBP3/TMEM219 axis, due to increased levels of circulating free IGFBP3, plays a key role in the exaggerated apoptosis of intestinal stem cells and pancreatic beta cells occurring in conditions of chronic gastrointestinal inflammation, such as Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (Figure 1). Therefore, the inhibition of the TMEM219/ IGFBP3 axis may represent an appropriate strategy to protect ISCs and pancreatic beta cells from the IGFBP3-mediated detrimental effects observed in IBD and T1D.

Development of a TMEM219 specific antibody with high affinity binding capacity.
In cooperation with Enthera YUMAB employed its proprietary fully human antibody platform and expertise to generate the lead candidate Ent001, a stabilized IgG4, without the need for bioinformatic engineering to reach an affinity to TMEM in the lower pM range. Ent001 specifically binds to TMEM219 inhibiting its interaction with IGFBP3 (Figure 2).

Antagonism of IGFBP3-binding to TMEM219 by Ent001 decreases apoptosis in preclinical models of IBD and T1D
With the lead antibody Ent001 YUMAB enabled Enthera to conduct successful preclinical development studies and to proceed with clinical trials in human. Ent001 is a first-in-class antibody targeting the IGFBP-3-TMEM219 axis. To date, Enthera successfully completed the evaluation of Ent001 for safety and tolerability in a Phase 1a first-in-human (FIH) study in healthy volunteers. The study results showed a safe and tolerable response upon Ent001 application without any adverse reactions. Tolerability is one of the key features of YUMAB’s fully human antibody platform. Based on these results Enthera initiated a multiple ascending dose Phase 1b clinical trial in patients with moderate to severe acute ulcerative colitis.