LYT-210

Our programs 1
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
LYT-210
Anti-Delta-1 MAb
Solid tumors

Preclinical

Solid tumors

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


Fully human IgG1 monoclonal antibody directed against the delta-1 chain of T cells bearing gamma delta-1 T cell receptors that we have designed to target and deplete immunosuppressive gamma delta-1 T cells in cancer.

Phase completedPhase in progressRegistration-enabling development plans in progress

1 The FDA and corresponding regulatory authorities will ultimately review our clinical results and determine whether our wholly-owned therapeutic candidates are safe and effective. No regulatory agency has made any such determination that LYT-210 is safe or effective for use by the general public for any indication.

Fully human monoclonal antibody targeting immunosuppressive and pathogenic γδ1 T cells for immuno-oncology

LYT-210 is a fully human IgG1 monoclonal antibody (mAb) directed against the delta-1 chain of T cells bearing gamma delta-1 T cell receptors (TCRs) that we have designed to target and deplete immunosuppressive gamma delta-1 T cells in cancer.

  • Key Points of Innovation & Differentiation
    • Immune checkpoint inhibitors, including therapies that target programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been developed to counteract multiple mechanisms of immune evasion by a number of different tumor types. Recent reports suggest that marketed drugs against these targets had sales exceeding $24 billion in 20192. Unfortunately, a large proportion of patients, especially those with immunologically silent tumors such as pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma (CCA), and some types of colorectal cancer (CRC), respond suboptimally to such agents.

     

     

    • We believe that gamma delta-1 T cells represent an important new IO target because they:
      • Activate multiple immunosuppressive pathways in the tumor microenvironment (TME);
      • Have expression correlated with poor outcomes for multiple solid tumor types; and
      • Target immunosuppressive gamma delta T cells, improved survival and reactivated cytotoxic T cells in the TME in the KPC orthotopic pancreatic cancer mouse model where approved checkpoint inhibitors are ineffective.
    • We are targeting the depletion of immunosuppressive, tumorigenic gamma delta-1 T cells rather than administration of cytotoxic gamma delta-2 T cells as a cell therapy. Gamma delta-1 T cells execute potent immunosuppressive function via multiple mechanisms, as illustrated on the left side of the figure above (LYT-210 gamma delta-1 mAb), which facilitates cancer progression. We have designed LYT-210 to eliminate gamma delta-1 T cells, and thereby potentially relieve immunosuppression, which we believe could enable immune mediated cancer attack.
  • Program Discovery Process by the PureTech Team
    • In order to identify approaches with the potential to provide significant therapeutic benefit to cancer patients, we 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. As a result of this search, and through our extensive network of advisors and collaborators, we identified a foundational immunosuppressive mechanism involving immunosuppressive gamma delta-1 T cells, which was the basis of LYT-210.
  • Patient Need & Market Potential
    • In the United States, there are approximately 57,000 new pancreatic cancer patients, of which 50 percent present with metastatic disease, approximately 146,000 new CRC patients, of which 35 percent present with metastatic disease, and approximately 8,000 new CCA patients, of which 50 percent present with metastatic disease, in each case, per year. Unfortunately, a large proportion of patients, especially those with immunologically silent tumors such as PDAC, CCA and some types of CRC respond suboptimally to immune checkpoint inhibitors, representing a significant patient population that has yet to receive benefit from any immuno-therapy agents.
  • Milestones Achieved & Development Status
    • Antibodies against gamma delta-1 T cells reactivated immunosuppressed T cells in the TME in patient-derived organoid tumors (PDOTs): To better assess the potential activity of the anti-delta-1 antibody, we employed PDOTs from primary and metastatic tumors spanning various solid tumor types such as pancreatic, CRC, CCA, hepatocellular cancer and neuroendocrine tumors of the gastrointestinal (GI) tract in order to assess the prevalence of tumor-infiltrating gamma delta-1 T cells and the capacity of the antibodies to restore tumor-infiltrating immune cell effector activity. We observed positive responses in approximately 60 percent of the PDOTs we analyzed, representing 19 patients, which showed that direct treatment of PDOTs with LYT-210 resulted in robust reactivation of effector T cells.
    • The figure below is illustrative of data collected from 19 human tumor organoid samples from CRC patients.

     

     

    • Absence of gamma delta T cells greatly increased survival in a pancreatic cancer mouse model: In order to assess the relevance of gamma delta T cells in the development and progression of pancreatic cancer, we assessed the survival of immunocompetent mice which have gamma delta T cells (wild type) in a KPC mouse pancreatic model. In addition, there was an additional group of wild type mice treated with an antibody, UC3-10A6, which functionally blocks immunosuppressive mouse gamma delta T cells. As shown in the figure below, when mice harboring pancreatic tumors are treated with an antibody against immunosuppressive gamma delta T cells, survival was greatly increased, as represented by the navy curve.

     

     

    • Mucosa-infiltrating pathogenic gamma delta-1 T cells may contribute to autoimmune diseases: Intraepithelial lymphocytes expressing gamma delta-1 TCRs are tissue-resident T cells that play a key role in homeostasis of the intestinal epithelium. It has been recently observed that chronic inflammation can permanently reconfigure the tissue-resident T cell compartment resulting in the repopulation of the GI mucosa with pathogenic and cytotoxic gamma delta-1 T cells. Establishment of pathogenic gamma delta-1 T cells along the GI tract tilts the gut environment towards a chronic inflammatory state, contributing to the pathophysiology of GI tract and inflammatory diseases, such as refractory celiac disease.
  • Expected Milestones
    • We are exploring additional biomarker studies for LYT-210 in 2021.
  • Intellectual Property
    • We have broad intellectual property coverage for these antibody-based immunotherapy technologies, including exclusive rights to three 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 use related immuno-oncology technologies and antibodies directed to pro-inflammatory gamma delta T cells for use in the treatment of inflammatory conditions, such as autoimmune disorders.
    • As of December 31, 2020, there are three families covering compositions of matter and methods of use for antibodies targeting gamma delta-1 T cells, including LYT-210, which are directed to the use of these antibodies for the treatment of cancer and one family directed to the use of these antibodies for the treatment of autoimmune disorders, for example, inflammatory bowel disease, ulcerative colitis, Crohn’s disease and celiac disease, among others. This intellectual property in total comprise one granted U.S. patent, three pending U.S. patent applications, one international PCT application and three foreign patent applications. Any patents issuing from pending applications with respect to LYT-210 are expected to expire in between 2037 and 2041, of which expiration dates are exclusive of possible patent term adjustments or extensions or other periods of exclusivity.

2 Van Arnum, Patricia, DCAT ValueChainInsights, Oncology Pharma Market: Immunotherapies on the Rise (2020).

3 Tool antibody that blocks mouse immunosuppressive gamma delta T cells.

LYT-210 is a novel, fully human mAb directed against T cells bearing γδ1 receptors, which are known to suppress the anti-tumor immune response. We presented promising preclinical data which demonstrated that LYT-210 is both highly specific and highly potent, rapidly inducing cell death of immune-suppressive γδ1 T cells, while sparing other T cells that play important roles in a healthy immune response. The research was conducted in vitro using both patient blood and cancer tissue. LYT-210 has potential as either a single agent or in combination with checkpoint inhibitors and other anti-cancer treatments.