Lymphatic-targeting chemistry platform leveraging the body's natural lipid absorption and transport process to orally administer drugs via the lymphatic system
Lymphatic-targeting chemistry platform leveraging the body's natural lipid absorption and transport process to orally administer drugs via the lymphatic system

Lymphatic-targeting chemistry platform leveraging the body's natural lipid absorption and transport process to orally administer drugs via the lymphatic system

  • We are advancing a synthetic lymphatic-targeting chemistry platform called Glyph, which is designed to employ the lymphatic system’s natural lipid absorption and transport process. We have now generated seven programs based on our Glyph platform including LYT-300, LYT-310 and LYT-320. Consumed nutrients and most orally administered pharmaceuticals are initially absorbed by the small intestine mucosa, distributed to the liver by the portal vein before entering systemic circulation. Importantly, many consumed dietary lipids, particularly triglycerides, enter systemic circulation by an alternate route. Triglycerides, which are composed of three fatty acid chains tethered to a 3-carbon glycerol molecule, are absorbed by small intestine mucosal enterocytes where they are incorporated into large lipid-protein complexes (chylomicrons) and released into the submucosa. Chylomicrons are too large to enter blood vessels and are instead taken up by submucosal lymphatic vessels. Once in the lymphatic vessels, they are transported to mesenteric lymph nodes associated with the gastrointestinal (GI) tract where they pass into larger lymphatic vessels connected to the thoracic duct, then merge with systemic circulation. This is in contrast to conventional systemic circulation via the gut and liver.
  • Our proprietary Glyph technology platform takes advantage of the fact that one of the triglyceride-associated fatty acids remains bound to dietary lipids during intestinal absorption, chylomicron conversion, lymphatic vessel uptake and eventual transport into the circulatory system. Using a modular set of proprietary chemical entities, small molecule pharmaceutical compounds can be attached to triglycerides where, following oral administration, the small molecule is directed into the mesenteric lymphatic system and on to systemic circulation. The process of drug release from the triglyceride is governed by self-cleaving chemical structures, with different release-timing features, that tether the small molecule to the module connected to the triglyceride.
  • Key Points of Innovation & Differentiation
    • We believe this platform provides the following capabilities:
      • Targeting the mesenteric lymphatics: This lymphatic targeting technology has important features that offer potential advantages in the creation of orally-administered medicines, especially those that need to reach immune system drug targets present in the GI tract mucosa and submucosa, such as intestine-associated immune cells, or in the mesenteric lymphatic vasculature, such as circulating immune cells, and mesenteric lymph nodes, such as lymph node stromal cells, antigen-presenting cells and lymph node-associated immune cells.
      • Enabling and enhancing oral bioavailability by bypassing first-pass metabolism: We believe this technology could provide a broadly applicable modular means to potentially enable oral administration of a range of bio-active natural molecules, such as neurosteroids, cannabinoids, and a large number of parenterally administered drugs, that are otherwise not orally bioavailable. This technology also has the potential to significantly enhance the bioavailability of orally-administered drugs that suffer from substantial first-pass hepatic metabolism, especially those utilized in combination therapies, that act as modulators (inducers and/or inhibitors) of drug-metabolizing systems in the liver.
    • To demonstrate the utility of our Glyph lipid prodrug platform, we chose a natural bio-active neurosteroid allopregnanolone as the subject of our inquiry, which has resulted in the LYT-300 program (see here). However, we believe that this benefit has the potential to be widely applied to nearly any natural molecules or therapeutic compatible with the synthetic approach which suffers from hepatic first-pass metabolism as has been evaluated by us and our collaborators.
  • Program Discovery Process by the PureTech Team
  • Milestones Achieved & Development Status
  • Intellectual Property
1 Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.
2 Cao, E., Watt, M.J., Nowell, C.J. et al. Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity. Nat Metab 3, 1175–1188 (2021).
3 Kochappan, R., Cao, E., Han, S., Hu, L., Quach, T., Senyschyn, D., Ferreira, V. I., Lee, G., Leong, N., Sharma, G., Lim, S. F., Nowell, C. J., Chen, Z., von Andrian, U. H., Bonner, D., Mintern, J. D., Simpson, J. S., Trevaskis, N. L., & Porter, C. J. H. (2021). Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice. Journal of Controlled Release, 332, 636–651.
4 PureTech retains rights to all other applications of this technology outside of the specific Boehringer Ingelheim candidates being studied.