Development of Novel Therapeutics for Chronic Inflammation by Leveraging Innate Lymphocyte Populations

Summary

• Irritable Bowel Disease (IBD) describes a complex collection of chronic inflammatory disorders which typically manifest as ulcerative colitis (UC) or Crohn’s disease
• While the incidence and prevalence of IBD has risen with modern human lifestyle changes (diet, smoking, antibiotics), the complex pathology involving microbe dysbiosis, immune imbalance, and persistent inflammatory activity remain largely unknown
• Dr. Sonnenberg has been at the forefront of interrogating the function, regulation, and therapeutic potential of a newly characterized population of tissue resident T- cells called group 3 innate lymphoid cells, or ILC3s.
• These MHC-II expressing cells play a critical role in establishing immune tolerance to gut microbiota via antigen presentation and selection of Treg cells adopting a tolerogenic vs. inflammatory fate in the intestine
• His pioneering work to understand the functional pathways which influence immune tolerance in the context of complex microbiota open new opportunities for IBD drug discovery platforms

Technical Overview

• ILC3s are widely distributed in the GI tract and airways, where they release soluble factors which modulate the clonal proliferation and differentiation of adaptive and mucosal immune cells
• Tumor Necrosis Factor (TNF), the primary therapeutic target in IBD, mediates pathogenic epithelial cell death and chronic intestinal inflammation
• ILC3s express the growth factor HB-EGF which protects intestinal epithelia from TNF-induced cell death and mitigates inflammation
• The Sonnenberg lab has in vivo proof of concept data showing that HB-EGF was essential in reducing epithelial cell death and inflammation in acute and chronic murine disease models
• Preclinical and clinical evidence suggest that selective activation of the ILC3-HB-EGF pathway provides an untapped avenue for target identification and development of inflammatory bowel disease therapeutics

Market Opportunity

• In 2020, the CDC estimated that 3.1 million Americans suffer from IBD and the global incidence has increased >40% since 2010
• IBD represents one of the fastest growing therapeutics markets, estimated at >$25B in 2023 and expected grow by CAGR of 5.7% between 2023 – 2030
• TNF inhibitors are the mainstay of IBD treatment, however 30% of patients are non-responders and up to 20% lose therapeutic response over time, highlighting an unmet need for these patients
• The Sonnenberg lab has evidence suggesting that pharmacological activation of HB-EGF-production by ILC3s in IBD has potential for disease modifying benefits in TNF refractory patients

Partnering Opportunity

Weill Cornell Medicine is seeking a partner in the IBD space to embark on a target / drug discovery campaign exploring the potential of ILC3s and developing agonists of therapeutic ILC3 pathways

Supporting Data / Figures

Figure 1: A: Schematic of TNF induced tissue damage and beneficial effect of the ILC3-HB-EGS axis. B: Induction of the ILC3/HB-EGF pathway.