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Eye on the prize
PARIS—TxCell SA , a biotechnology company developing personalized T cell immunotherapies using antigen-specific regulatory T cells (Ag-Tregs) for severe chronic inflammatory and autoimmune diseases, has published the preclinical efficacy results for Col-Treg—TxCell’s second therapeutic candidate from its ASTrIA platform—to treat non-infectious uveitis. The results are being published in Investigative Ophthalmology & Visual Science (IOVS), a prominent journal in the field of ophthalmic and vision research.
Entitled “Inhibition of non-infectious uveitis using intravenous administration of collagen-II specific Type 1 regulatory (Col-Treg) T cells,” the study evaluated the therapeutic potential of Col-Treg immunotherapy for the treatment of non-infectious uveitis using in-vitro and in-vivo assays.
Specifically, in-vivo administration of Col-Treg in the model of autoimmune uveitis significantly inhibited clinical symptoms, retinal tissue lesions and ocular proinflammatory cell infiltration.
The authors also dissected the mechanism of action of Col-Treg, showing that cells are using several distinct immune-regulatory pathways to dampen inflammation.
Col-Treg is a personalized T cell immunotherapy product, based on the properties of autologous collagen II-specific regulatory T lymphocytes, according to the authors. In addition, Col-Treg has shown very promising preclinical efficacy and tolerability data in models of inflammatory arthritis, according to Arnaud Foussat, chief scientific officer of TxCell, who adds: “Following the previous demonstration of Col-Treg preclinical efficacy in models of inflammatory arthritis, these results published in IOVS demonstrate the therapeutic potential of Col-Treg in non-infectious uveitis and will support its ongoing clinical development.”
“The support TxCell has seen from the ophthalmologic community provides additional confirmation of the potential of, and requirement for, Col-Treg as a much-needed new potential treatment for autoimmune uveitis, a rare and debilitating eye disease with very limited therapeutic options,” Foussat stated in a news release about the research results.
“There are approximately 30,000 autoimmune uveitis patients per year that are refractory to approved steroids treatments in the U.S. and Europe alone, and this is a clear unmet medical need,” he says.
Col-Treg has been classified as an Advanced Therapy Medicinal Product by the European Medicine Agency (EMA). Col-Treg also received an Orphan Drug Designation for the treatment of non-infectious (autoimmune) uveitis from the EMA in December 2014. A first-in-human clinical study with Col-Treg for severe autoimmune uveitis patients that become refractory to steroid compounds is scheduled to start in 2016, according to Foussat.
Autoimmune uveitis is a serious inflammatory condition of the eye and often results in permanent vision damage. Uveitis is classified as a rare disease. Yet, despite its rarity in developed countries, this autoimmune disease causes 10 to 15 percent of legal blindness.
TxCell has created ASTrIA, a proprietary product platform based on the properties of autologous antigen-specific regulatory T lymphocytes (Ag-Tregs). The company has initiated a Phase 2b study of its lead product candidate, Ovasav, in refractory Crohn’s disease patients. This follows a Phase 1/2a study in the same patient population reporting positive clinical efficacy and good tolerability. TxCell’s second product candidate is Col-Treg for the treatment of autoimmune uveitis.
To evaluate the therapeutic potential of Col-Treg in this preclinical study, a collagen II-specific type 1 regulatory T cell immunotherapy for the treatment of noninfectious uveitis (NIU), Col-Treg cells were produced from collagen II-specific T cell receptor (TCR) transgenic mice or peripheral blood of healthy donors.
Phenotypic characterization was performed by flow cytometry, and cytokine secretion was evaluated with Flowcytomix or ELISA. In-vitro functional characterization included ATP hydrolysis, cytotoxicity and contact-independent T cell suppression and plasticity assays. Col-Treg migration was assessed by quantitative PCR specific to Col-Treg TCR. Col-Treg cells were administered intravenously in mice displaying experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein immunizations. Efficacy of Col-Treg was assessed by ophthalmology, histology and immunohistochemistry.
Mouse Col-Treg cells displayed identity features of type 1 Treg cells with expression of CD25, FoxP3, low surface expression of CD127 and cytokine secretion profile (IL-10high, IL-4low, IFN-γint). In-vitro functional assays demonstrated Col-Treg suppressive capacity via soluble factor-dependent immunosuppression, cytotoxicity and ATP hydrolysis. Col-Treg cells expressed granzyme B, CD39 and glucocorticoid-induced TNF-related protein (GITR). Administration of Col-Treg in EAU mice inhibited clinical and morphologic signs of uveitis and decreased ocular leukocyte infiltration. Col-Treg cells homed in the ocular tissues 24 hours after intravenous injection. Human Col-Treg cells were comparable to mice Col-Treg cells in identity and function and did not show the capacity to differentiate into Th17 cells in vitro.
As the IOVS paper concludes: “These results demonstrate the therapeutic potential of Col-Treg cells as a targeted approach for the treatment of NIU and the feasibility of translating this approach to the human clinical setting.”