LYT-200

 

Our programs
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
LYT-200
Anti-Galectin-9 MAb
Solid tumors
IND and initiation of Phase 1 study in 2020

Preclinical

Solid tumors

>50K/year U.S. (Metastatic CRC)
>28K/year U.S. (Metastatic pancreatic cancer)
>4K/year U.S. (Metastatic cholangiocarcinoma)


LYT-200 is an investigational, fully human, IgG4 monoclonal antibody (mAb) that is designed to target galectin-9, a protein that regulates immunosuppression and is prominently expressed in hard-to-treat cancers, such as colorectal cancer, or CRC, cholangiocarcinoma, pancreatic cancer and others.

Phase completedPhase in progress
Monoclonal antibody aimed at galectin-9, a fundamental modulator of the immune system 

LYT-200 is an investigational, fully human, IgG4 monoclonal antibody (mAb) that is designed to target galectin-9, a protein that regulates immunosuppression and is prominently expressed in hard-to-treat cancers, such as colorectal cancer, or CRC, cholangiocarcinoma, pancreatic cancer and others.

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.

  • Program Discovery Process by the PureTech Team
    • PureTech undertook a global, proactive search to discover important new scientific insights and technologies that could address the challenge of multiple mechanisms of immunosuppression in current therapeutics. Through this process, PureTech identified the pioneering work of George Miller, MD, at New York University. PureTech began collaborating with Dr. Miller prior to his ground-breaking research being published in Cell and Nature Medicine. The publications demonstrate the role of newly discovered immunosuppressive mechanisms involving galectin-9, which was the basis of developing LYT-200.
  • Patient Need & Market Potential
    • Each year in the US there are approximately:
      • 57,000 new pancreatic cancer patients, of which 50 percent present with metastatic disease;
      • 146,000 new CRC patients, of which 35 percent present with metastatic disease; and
      • 8,000 new cholangiocarcinoma patients, of which 50 percent present with metastatic disease.
    • These all represent significant patient populations that have yet to receive benefits from any immuno-therapy agents.
  • Innovative Approach to Solving the Problem
    • LYT-200 is an investigational, fully human IgG4 mAb that is designed to block galectin-9, which PureTech is developing for the treatment of solid tumours, including CRC, pancreatic cancer, cholangiocarcinoma and others that do not respond to approved checkpoint inhibitors and have poor survival rates.
    • PureTech believes LYT-200 holds potential as an immuno-oncology therapeutic because galectin-9:
      • Polarizes macrophages from the M1 to M2 phenotype, induces apoptosis of cytotoxic CD8+ T cells and facilitates expansion of and immunosuppression via Tregs and myeloid derived suppressor cells (MDSCs);
      • Has high expression that correlates with poor outcomes for multiple solid tumor types as well as resistance to approved checkpoint inhibitors;
      • Has preclinical evidence using a reagent anti-galectin-9 antibody that showed improvement in survival in a KPC pancreatic cancer mouse model where, like their human counterparts, checkpoint inhibitors have failed. PureTech has since obtained data using LYT-200 in pancreatic cancer and melanoma rodent models where administration of LYT-200 led to greater tumour reduction and activity than an anti-PD-1 antibody as well as in patient-derived organoid, or PDOT, systems;
      • While elevated in the context of cancer, galectin-9 has low expression under normal physiological conditions, indicating a potential safety window which has been further supported by the lack of tolerability concerns to date in PureTech’s studies with LYT-200, even at extremely high doses such as 300 mg/kg in non-human primates.
  • Intellectual Property
    • PureTech has broad intellectual property coverage for this antibody-based immuno-therapy technology, including exclusive rights to four families of patent filings that are exclusively licensed from or co-owned with New York University, which cover antibodies that target immunosuppressive agents and mechanisms and methods of use for the treatment of solid tumors, such as pancreatic cancer, CRC, melanoma, gastric cancer, breast cancer and various other cancers.
    • As of 31 December 2019, there are three families of intellectual property within this patent portfolio covering compositions of matter and methods of use for antibodies targeting galectin-9, including LYT-200. These three families comprise in total two issued U.S. patents which are expected to expire in 2038, 13 pending U.S. patent applications, which, if issued, are expected to expire in 2038 through 2040 and one international PCT application.
    • In addition, there is one family of intellectual property covering compositions of matter and methods of use for related immuno-oncology technologies, which in total comprises three pending patent applications in US and foreign jurisdictions. This family is expected to expire in 2037. All expiration dates are exclusive of possible patent term adjustments or extensions or other periods of exclusivity.
  • Milestones Achieved
    • In June 2020, PureTech presented new data at the American Association for Cancer Research (AACR) 2020 Virtual Annual. The data established galectin-9 as a novel target for cancer immunotherapy and provided compelling evidence that therapies targeting galectin-9 may enable the immune system to attack an array of solid tumors. The research also established galectin-9 as an important biomarker for patient stratification.
    • In November 2019, PureTech presented new preclinical data at the Society for Immuno-therapy of Cancer (SITC) 34th Annual Meeting. The presented data indicated that galectin-9 is not only a potent therapeutic target, but also a potentially relevant biomarker. Across multiple cohorts, galectin-9 was significantly increased in blood samples of individuals with primary and metastatic pancreatic cancer, lung tumors and colorectal carcinoma, compared to healthy individuals.
  • Expected Milestones
    • PureTech expects to file an IND for LYT-200 and to initiate a Phase 1 study in solid tumors in the second half of 2020, with results anticipated in 2021. The planned clinical trial is a Phase 1 open label non-randomized clinical trial of LYT-200 alone or in combination with chemotherapy or an approved anti-PD-1 agent in relapsed/refractory metastatic patients.

PureTech’s LYT-200 targets galectin-9 for the potential treatment of a range of cancer indications. Galectin-9 is a foundational immunosuppressive protein that is prominently expressed in a number of cancers, especially in hard-to-treat cancers, such as colorectal and pancreatic cancer and cholangiocarcinomas.

 


Galectin-9 triggers and mediates multiple pathways of immunosuppression

Foundational biology

Affects multiple pathways of immunosuppression, potentially enabling a single-agent therapeutic

Proof-of-concept in preclinical models

  • Tumor reduction in pancreatic cancer model where anti-PD1 has failed
  • Outperforms anti-PD1 in standard checkpoint inhibitor (CPI) responsive melanoma model
  • Restoration of T cell activity in patient-derived organoids

Biomarker opportunity

Expression increased in blood and tissue of multiple tumor types, correlating with adverse prognosis


Image adapted from J Mol Biol; 428 (16): 3266-3281; 2016

Treg = T regulatory cell; MDSC = myeloid derived suppressor cell; M1/M2 = tumor associated macrophage (TAM)1 (immunoactive) and 2 (immunosuppressed) cell; Th1 = T helper1 cell


The below figure on the left depicts LYT-200 mouse mAb activity in an orthotopic pancreatic cancer KPC model

KPC cells were engrafted into the pancreata of immunocompetent mice and were treated systemically with the mouse version of the LYT-200 antibody, or LYT-200 mouse mAb. PureTech observed significant tumor growth reduction at the end of the experiment with LYT-200 mouse mAb as a single agent (p < 0.01) as assessed by decrease in tumor weight. The below figure in the middle illustrates examples of in vitro T cell activation with LYT-200.

Single agent activity in KPC (pancreatic cancer) model

A model where anti-PD1s do not work 


T cell activation with LYT-200 in patient-derived organoid model



LYT-200 drug properties make it an excellent clinical clone

  • High affinity and specificity for galectin-9
  • Desired function: Blocking galectin-9 mediated immunosuppression
  • Robust activity in preclinical studies:
    • Single agent causes tumor reduction in pancreatic and melanoma mouse models
    • Observed ~50% tumor reduction with LYT-200 vs. ~22% tumor reduction with anti-PD1 in melanoma model
    • Increase in intra-tumoral CD8 T cells in combination with anti-PD1
    • Activation of intra-tumoral immunity in patient-derived tumor models

 



Note: For patient-derived organoids, n = 23 tumor samples; Success defined as: >20% upregulation of at least two out of three T cell activation markers; success achieved in 60% of tumors with majority showing >2 fold activation