On April 2, 2019 PureTech Health plc (LSE: PRTC) ("PureTech Health"), an advanced biopharmaceutical company developing novel medicines for dysfunctions of the Brain-Immune-Gut (BIG) axis, reported the presentation of two scientific posters at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Atlanta, Georgia (Press release, PureTech Health, APR 2, 2019, View Source [SID1234534918]).
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Joseph Bolen, PhD, chief scientific officer at PureTech Health, said: "PureTech Health has built a leading position in BIG therapeutic development through its affiliate technologies and is now capitalizing on this critical mass of expertise through multiple internal development programs that are delivering clinical candidates. We’re proud to present data on these programs at AACR (Free AACR Whitepaper), one of the premiere scientific meetings focused on cancer research. Galectin-9 and γδ1 T cells represent powerful immunosuppressive mechanisms across both innate and adaptive immunity. We have moved quickly to advance development of compelling candidates that could act as both monotherapies and combination therapies against cancers that currently do not respond well to approved immunotherapies. In addition to our programs targeting the body’s immune cell trafficking highway – the lymphatic system – these immuno-oncology programs round out an exciting pipeline of therapeutics targeting important regulators of the immune system."
The posters detail the Company’s development of first-in-class, fully-human monoclonal antibodies (mAbs) targeting Galectin-9 (LYT-200) and immunosuppressive γδ1 (gamma delta) T cells (LYT-210). LYT-200 and LYT-210 are unique mAbs targeting foundational, novel mechanisms of tumoral immune escape and immunosuppression in cancer, and have been tested as single agents, as well as in combination with anti-PD1 in preclinical murine and human-derived ex vivo models. As such, they represent novel additions to the armamentarium of immuno-oncology agents, with potential across multiple solid tumors including malignancies that have historically proved difficult to treat. The AACR (Free AACR Whitepaper) posters describe their development, lead candidate characterization, and pre-clinical efficacy models.
Galectin-9 is a master immunosuppressor that affects multiple cell types (e.g., regulatory and effector T cells, myeloid-derived suppressor cells, and macrophages) to induce and maintain a tumor-permissive microenvironment. As it can be both expressed by cancer cells and present in cancer tissue, and it can also be secreted into the circulation of cancer patients, targeting Galectin-9 can enable multiple anti-tumor effects. PureTech’s anti-Galectin-9 antibody, dubbed LYT-200, is being developed for difficult-to-treat malignancies, including pancreatic, cholangiocarcinoma, and certain types of colorectal and liver cancers, which remain insufficiently responsive or resistant to currently approved checkpoint inhibitors. The research presented today details the development and comprehensive characterization of LYT-200 and its efficacy in preclinical human-derived ex vivo models and a murine model. The work demonstrates efficacy to reduce tumor growth, as well as the ability of LYT-200 to reactivate human effector T cells in patient-derived tumor culture models.
Gamma Delta 1 (γδ1) T cells are an immunosuppressive subset of the γδ T cell family of immune cells, which are upregulated in multiple solid tumors including breast cancer, glioblastoma, melanoma, and pancreatic cancer. Notably, an abundance of circulating γδ1 T cells has been associated with poor response to checkpoint therapy in melanoma patients. γδ1 T cells harbor a distinct phenotype characterized by expression of the δ1 chain in the T cell receptor. Immunosuppressive γδ1 T cells function to block effector T cells, restrict anti-tumoral γδ2 T cell subset, hinder antigen-presenting dendritic cells, and attract tumor-associated macrophages and myeloid-derived suppressor cells to enhance immunosuppression in cancer. Targeting γδ1 T cells therefore has the capacity to modulate both innate and adaptive immunity, and their distinct phenotypic and functional properties make them excellent therapeutic targets in cancer. The research presented today focuses on PureTech’s leading antibody candidate aimed at depleting γδ1 T cells, showing high specificity (e.g., binding to δ1 but not the δ2 chain present on cytotoxic γδ T cells), excellent binding affinity to both human and non-human primate δ1 chains, as well as functional properties to increase T cell effector activity in human derived ex vivo models. PureTech Health believes its anti-δ1 mAb program is the only one of its kind, and the Company is now finalizing the program’s lead clinical candidate selection.
The company anticipates filing an Investigational New Drug Application (IND) for LYT-200, which targets Galectin-9, in 2020 and anticipates continuing to advance the lead clinical candidate of the γδ1 program, LYT-210, into development