Science

Obsidian Therapeutics is developing a suite of technologies that allow for exquisite control of protein activity in cells, thereby enabling tunable cell and gene therapies. These technologies will enable the creation of a powerful new class of therapies that address the safety and efficacy limitations of existing treatments, and allow for new approaches to treating cancer and other diseases.

Obsidian's Approach to Regulating Gene Therapy

Obsidian uses Destabilizing Domains (DDs) to enable pharmacologic regulation of the expression of transduced genes. 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. This approach has many potential advantages over other methods of regulating transgene expression, which largely rely on transcriptional regulation via inducible promoters. The unique benefits of Obsidian’s DD approach include:

  • Safety feature of gene therapy’s default state being OFF, with undetectable protein levels
  • Activation of protein expression with separately administered, FDA-approved, oral drugs with well-characterized pharmacokinetics
  • Rapid, dose-responsive induction and dependable decay after cessation of ligand administration
  • Ability to regulate the expression of proteins with many different structures and functions

Obsidian is using DDs to create cell therapies with regulated cell-surface receptors, secreted cytokines, cytoplasmic, and nuclear proteins. We have designed our two-part therapeutic system – with a synthetic biological cassette in the cell therapy and the small molecule drug that controls the cassette’s activity – to be a simple and elegant method of regulating transgene function that has the potential to unlock the power of adoptive cell transfer in oncology and eventually find broad use in all forms of cell and gene therapy.

Advancing the Platform

Obsidian has taken the original work on destabilizing domains (DDs) performed by our scientific founder, Professor Thomas Wandless, and has substantially advanced the platform. We have created libraries of novel DDs with properties that make them more suitable for therapeutic use, including:

  • Regulation via FDA-approved and non-immunosuppressive small molecule drugs
  • DDs based on native human proteins to reduce potential immunogenicity
  • Differential on-off characteristics to allow for rheostat functionality
  • Optimized basal “off” state characteristics
  • Cleavable linkers

POWERING UP ADOPTIVE CELL THERAPY FOR CANCER

Control of gene expression is a key issue for adoptive immunotherapy because current technologies do not allow titration of the timing or levels of therapeutic activity. This has made many potential applications difficult or impossible to deploy safely and effectively. The lack of tunability also makes it difficult to safely express potent proteins with narrow therapeutic windows or transient expression.

Obsidian’s current focus is Adoptive Cell Therapy (ACT) for cancer, where tremendous progress has been made in recent years but where today’s therapies remain difficult to titrate, control, or modulate. Among the challenges with current approaches are:

  • Need for intensive chemotherapy to “precondition” patients prior to therapy
  • Lack of control over cell expansion after administration to patients, leading to limited control of toxic side effects, such as cytokine release and neurotoxicity
  • Limited penetration into solid tumors
  • Tonic cell signaling leading to upregulation of suppressive factors, immune effector cell anergy, and antigen escape

Obsidian’s initial areas of drug development include creating synthetic biological cassettes that incorporate controllable functions for inclusion in CAR-T and CAR therapies. In these applications, using DD technology enables control of key functions to improve safety and efficacy in ways that are not possible with existing CAR-T treatments. Our initial programs include:

  • Adoptively transferred lymphocytes with regulated cytokines, to help manage cell expansion and penetrance into solid tumors
  • Regulated CARs, to allow for precise titration of therapy and to avoid T cell anergy
  • Novel safety switches, to provide a “rescue” path in the event of unmanageable toxicity