Obsidian Therapeutics, Inc., a biotechnology company dedicated to the development of next-generation cell and gene therapies with pharmacologic operating systems, today announced that the company presented preclinical data on its regulated IL12 and IL15 programs at the Annual Meeting of the American Society of Gene and Cell Therapy in Chicago, IL.
Obsidian is developing CAR-T therapies that incorporate Destabilizing Domains (DDs) to regulate expression of immune cytokines, thereby providing pharmacologic control over these potent but potentially toxic molecules. 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. IL12 and IL15 are two important immune cytokines that play important roles in tumor response to adoptive cell therapy but which require precise control to optimize their therapeutic benefit.
"IL12 and IL15 are critical factors that promote CAR-T cell expansion, persistence, and penetration into solid tumors," said Vipin Suri, Ph.D., Vice President of Discovery of Obsidian. "However, unregulated expression of these cytokines by CAR-T or other adoptively-transferred cells can potentially compromise safety and efficacy. Obsidian's technology allows the treating physician to control expression of IL12 and IL15 via the use of safe, FDA-approved small-molecule drugs, and the preclinical data we present today demonstrate the elegance and effectiveness of this approach."
Highlights of the two preclinical presentations follow:
Abstract number 113: Exogenous In Vitro and In Vivo Regulation of Interleukin-12 Secretion from T Cells Using Destabilizing Domain Technology
Presenter: Dexue Sun
Session: Cancer - Immunotherapy, Cancer Vaccines I
- Construction of a single-chain regulated IL12 using a DD derived from FKBP
- Demonstration of small molecule-regulated expression of IL12 in a variety of cell types including primary human T cells
- Use of different promoters to tune expression level of the regulated cytokine
- Demonstration of in vivo regulation of IL12 in adoptively transferred T cells
- Development of a CD19 CAR construct co-expressing regulated IL12, with in vitro data showing effective performance of the regulated cytokine cassette
Abstract number 133: Dose dependent exogenous regulation of membrane bound Interleukin-15-Interleukin-15 receptor alpha fusion protein for adoptive T-cell therapy
Presenter: Christopher Reardon
Session: Cancer - Targeted Gene & Cell Therapy I
- Design of regulated membrane-bound IL15-IL15 Receptor Alpha (mbIL15) fusion construct incorporating DDs for pharmacologic control with small molecule ligands
- Construction of mbIL15-DD construct incorporating human DDs, regulated by FDA-approved small-molecule drugs
- Dose- and time-dependent regulation of mbIL15 expression in multiple cell types
- Regulation of mbIL15 expression on primary human T cells in vivo