Obsidian Therapeutics, Inc., a biotechnology company dedicated to the development of next-generation cell and gene therapies with pharmacologic operating systems, today announced the presentation of preclinical data on its regulated cytokine programs at the Annual Meeting of the American Association for Cancer Research in Chicago, IL.

The poster presentation includes in vivo data demonstrating Obsidian’s use of destabilizing domains (DDs) to regulate expression of important immune cytokines, demonstrating the potential to create CAR-T therapies that incorporate controllable functions for enhanced safety and efficacy. DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein that is engineered into a cell or gene therapy product.

"We are excited to present this important data update on our regulated cytokine programs," said Celeste Richardson, PhD, Vice President and Head of Cell Therapy for Obsidian, who presented the poster at AACR. "While CAR-T and TCR-T have shown impressive promise to date, we believe that our approach with destabilizing domains opens new ways to improve these therapies with pharmacologic operating systems. We are empowering these cell therapies with new functionalities that are controllable by the treating physician, thereby enabling a new generation of safer and more effective cancer treatments."

The AACR presentation describes the use of DD technology in engineered primary human T cells to control expression of critical immunocytokines in vitro and in vivo, with evidence of in vivo immunephenotypic changes resulting from activation of the regulated cytokine cassettes. The data demonstrate the utility and flexibility of DD technology in regulating both secreted and membrane-bound proteins, which can enable the development of next-generation CAR-T cell products with enhanced efficacy and more favorable safety profiles. Data presented at the meeting include:

Use of Obsidian’s Destabilizing Domain (DD) discovery engine to create libraries of novel human DDs controllable with FDA-approved small-molecule drugs as pharmacologic regulators, with a wide range of performance characteristics.

Demonstration of kinetic and concentration-dependent regulation of IL12 with a prototype DD system in primary human T cells, both in vitro and in vivo.

Ability to repeatedly activate the DD-IL12 system in vivo with consistent kinetics and peak cytokine concentrations.

Phenotypic changes that result from activation of the DD-IL12 system in vivo, including changes in granzyme B and perforin expression in CD8 cells.

In vitro and in vivo regulation of a membrane-bound IL15 construct in primary human T cells, with concentration-dependent protein expression using clinically-achievable doses of an FDA-approved drug.

These studies show Obsidian’s ability to achieve precise kinetic and dose-responsive control over transgene-derived protein expression, which enables the development of next generation CAR-T cell products with enhanced efficacy and more favorable safety profiles.

About Destabilizing Domains
Obsidian uses Destabilizing Domains (DDs) to enable pharmacologic regulation of protein activity for next-generation cell and gene therapies. Obsidian’s DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein. In the absence of a specific small-molecule ligand, the fusion protein is rapidly degraded, whereas in the presence of the ligand, the fusion protein becomes stable and functional. Obsidian uses this approach to equip engineered cells with controllable functions that can be precisely tuned by the administration of non-immunosuppressive, small-molecule medicines that are readily available and dispensed by the treating physician.

About Obsidian Therapeutics
Obsidian Therapeutics is a biotechnology company developing next-generation cell and gene therapies with pharmacologic operating systems. Based upon founding work on destabilizing domains by Professor Thomas Wandless, a leading researcher in chemical and systems biology, Obsidian’s lead programs are CAR-T products that incorporate controllable functions for enhanced safety and efficacy. Obsidian was founded in 2015 by Atlas Venture and is funded by a strong syndicate of venture investors. 

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