Lymphatic Targeting Chemistry Platform

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Lymphatic Targeting Chemistry Platform
Orphan & other
neurological indications

A synthetic lymphatic targeting chemistry platform being developed to employ the body’s natural lipid absorption and transport process to orally administer drugs via the lymphatic system by (1) targeting the mesenteric lymph nodes and (2) bypassing first-pass metabolism.

Phase completedPhase in progress
Lipid prodrug technology designed to employ natural lipid absorption and transport process to enable lymphatic targeting

PureTech is developing a synthetic lymphatic targeting chemistry platform that employs the body’s natural lipid absorption and transport process to orally administer drugs via the lymphatic system by (1) targeting the mesenteric lymph nodes and (2) bypassing first-pass metabolism. 

Consumed nutrients and orally-administered pharmaceuticals are initially absorbed by the small intestine mucosa and 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 called 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 gastro-intestinal (GI) tract where they pass into larger lymphatic sinuses connected to the thoracic duct, then transition to systemic circulation. This is in contrast to conventional systemic circulation via the gut and liver. 

We are advancing a broad pipeline of programs to treat cognitive deficiency and improve symptoms associated with medical conditions across neurology and psychiatry, including attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), autism spectrum disorder (ASD), multiple sclerosis (MS) and various other neuroinflammatory diseases. We are also developing associated clinical monitors and measurement-based care applications. Our lead, patented technology platform is exclusively licensed from the lab of Dr. Adam Gazzaley at the University of California, San Francisco (UCSF), and augmented by proprietary adaptive algorithms developed by our team.

  • Innovative Approach to Solving the Problem
    • PureTech’s lymphatic targeting technology has important features potentially offering meaningful advantages in the creation of orally-administered medicines, especially those that need to reach immune system drug targets that are present in the GI tract mucosa and submucosa (e.g., intestine-associated immune cells), or in the mesenteric lymphatic vasculature (e.g., circulating immune cells) and mesenteric lymph nodes (e.g., lymph node stromal cells, antigen-presenting dendritic cells (DCs) and lymph node-associated immune cells). The 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 docked to triglycerides where, following oral administration, the small molecule is directed into the mesenteric lymphatic system and on to systemic circulation The point of original small molecule 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.
    • Targeting the Mesenteric Lymph Node
      • To demonstrate the mesenteric lymphatic targeting capability of the platform, prodrugs were created from unmodified mycophenolic acid (MPA), which is an immune-suppressive agent widely used in solid organ transplant rejection therapy and the treatment of lupus autoimmunity. Preclinical studies in rodent models conducted by one of the co-inventors of this technology and a PureTech collaborator, Chris Porter, PhD, at Monash University, and subsequently reproduced by PureTech, demonstrated that lipid prodrugs of MPA were capable of achieving MPA concentrations in mesenteric lymph, mesenteric lymph nodes and in mesenteric lymph node immune cells that were ten to 100-fold higher than observed with unmodified MPA.
    • Enhancing Oral Bioavailability
      • This technology could provide a broadly-applicable modular means to significantly enhance the bioavailability of orally-administered drugs that suffer from substantial first-pass liver metabolism or those drugs, especially those utilized in drug combination therapies, that act as modulators (inducers and/or inhibitors) of drug-metabolizing systems in the liver. To explore the utility of the platform in such cases, PureTech has created several lipid prodrugs of allopregnanolone, an inhibitory pregnane neurosteroid that acts as a highly potent positive allosteric modulator of the GABAA receptor and is approved by the FDA as a 60-hour infusion for the treatment of postpartum depression under the brand name Zulresso. PureTech demonstrated that oral-dosing of these prodrugs achieved therapeutically relevant plasma levels in small and large animal models. Coupled with other preclinical studies, these results support the possible utility of this approach for converting allopregnanolone into an orally-dosed drug as well as for numerous other potential therapeutics with intrinsic hepatic metabolism liabilities and/or oral absorption limitations.
      • To date, PureTech has successfully extended the platform to encompass more than 20 potential product candidates as well as a range of novel linker chemistries that have demonstrated promising lymphatic targeting in preclinical studies. From this work, PureTech may be able to nominate a prodrug candidate as soon as the first half of 2020.
      • Additionally, PureTech announced an alliance with Boehringer Ingelheim in April 2019, which is initially focused on evaluating the feasibility of applying its lymphatic targeting technology to one of Boehringer Ingelheim’s immuno-oncology product candidates. Under the terms of the agreement, PureTech is eligible to receive up to $26 million in upfront payments, research support, and preclinical milestones, and is eligible to receive more than $200 million in development and sales milestones, in addition to royalties on product sales. PureTech retains all other applications of this technology.
  • Collaborations
    • In April 2019, PureTech announced an alliance with Boehringer Ingelheim (BI), which is initially focused on evaluating the feasibility of applying PureTech’s lymphatic targeting technology to one of BI’s immuno-oncology product candidates. Under the terms of the agreement, PureTech is eligible to receive up to $26 million in upfront payments, research support and preclinical milestones, and is eligible to receive more than $200 million in development and sales milestones, in addition to royalties on product sales.
  • Intellectual Property
    • PureTech has broad intellectual property coverage for its proprietary lymphatic targeting platform, which includes exclusively licensed and co-owned patent applications, as well as company-owned patent applications. These patent applications cover compositions of matter, methods of use and methods of treatment encompassing specific chemical modifications, including a wide range of novel linker chemistries, as well as various classes of lymphatic targeting therapeutics, which include prodrugs for a large number of active pharmaceutical ingredients (APIs), for use in the treatment of a wide range of diseases and disorders. As of 31 December 2019, PureTech’s lymphatic targeting platform intellectual property portfolio consists of 17 patent families comprising 15 U.S. patent applications, four international PCT applications and ten foreign patent applications. Of these, company-owned IP consists of eight U.S. patent applications in six patent families. PureTech exclusively licensed and co-owns a patent portfolio of 11 patent families comprising 18 U.S. and foreign patent applications and four international PCT applications from Monash University. Any issued patents from the in-licensed patent applications are expected to expire in 2035 through 2036 and any issued patents from the co-owned and company-owned patent applications are expected to expire in 2038 through 2040, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.

Conventional drug circulation versus lymphatic systemic circulation