13 November 2018 - - US-based biotechnology company Obsidian Therapeutics, Inc has presented preclinical data demonstrating fine-tuned regulation of cytokine production and CAR-T function using Destabilizing Domains paired with FDA-approved small molecule drugs, the company said.

Obsidian revealed a suite of novel human DDs and showcase their application in CAR-T therapy at the Society for Immunotherapy of Cancer's 33rd annual meeting in Washington, DC, November 7-11, 2018.

DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein. These regulated cassettes can be readily added to a cell or gene therapy product.

CAR-T cells are engineered to find and destroy tumor cells and can be armed with powerful cytokines, such as IL12 and IL15, to further enhance anti-tumor immunity.

However, these potent immune modulators require precise control to optimise their therapeutic benefit.

Highlights of two preclinical presentations describing Obsidian's enhanced CAR-T therapies were included.

The company said it had achieved titratable, fine-tuned regulation of IL12 and IL15 in human T cells in vitro and in vivo with clinically translatable DDs and FDA-approved drugs.

DDs provide small molecule regulation of CAR expression and activity in T cells.

In the second presentation, the company said it demonstrated on-demand anti-tumor activity of a clinically translatable DD-CAR in T cells with drug dosing in vivo.

These studies show Obsidian's ability to achieve precise kinetic and dose-responsive control over transgene-derived protein expression, fueling the development of CAR-T cell therapies that are potentially safer and more efficacious.

Obsidian uses Destabilizing Domains 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.

Obsidian Therapeutics is a biotechnology company developing next-generation cell and gene therapies with pharmacologic operating systems.

Based upon founding work on destabilising domains by Professor Thomas Wandless, a 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. The company is headquartered in Cambridge, Massachusetts.