Universal Synapse Enhancing Domain (PDZbm) (SJ-22-0011)

St. Jude Reference #SJ-22-0011

Description

Chimeric antigen receptor (CAR) technologies have been successfully implemented in the clinic for the treatment of hematological malignancies. However, solid tumors remain resilient to CAR-based cell therapeutics. Researchers at St. Jude sought to improve the ability of CARs to activate immune cells by adding a scaffolding protein binding site, specifically a PDZ binding motif, to the C-terminus of the CAR. Thus, our invention consists of a CAR design that contains a novel PDZ binding motif to enhance cell therapies.

Current CAR designs create a disordered and inefficient immune synapse which can lead to cellular exhaustion and therapeutic failure from antigen loss on target cells. This novel design allows for multifactorial problems to be solved with the anchoring of the CAR to the internal scaffolding proteins inside the effector cell. This PDZ binding motif constitutes a novel domain for CAR therapeutics. This anchoring domain can be incorporated into current clinical CAR designs to enhance their efficacy and be readily translated for therapeutic use.

Compared to standard CARs, this new design helps to form a more efficient synapse that increases cytotoxicity and anti-tumor activity of CAR-NK and CAR -T cells. Additionally, this domain was independently screened by Modulus Therapeutics and the incorporation of the PDZbm led to their best design in vivo in pre-clinical models of B-cell leukemia. This mirrored our results in numerous solid tumor and intractable brain tumor models.

This invention is a universal augmentation that can be utilized to enhance existing CAR designs. While we mainly demonstrate its utility in NK and T cells, this design could be applied to a broad range of immune cells that are currently being developed, for example but not limited to: macrophages, B cells, neutrophils, HSC, IPSC, and CB derived stem cells, ab T cells, γδ T cells, or iNKT cells.

Keywords

Immunotherapy, chimeric antigen receptor (CAR), scaffolding protein binding, PDZ binding motif, CAR, C-terminus, B cells, macrophages, IPSC, HSC, cord blood, NK cells, ab T cells, γδ T cells, or iNKT cells, solid tumor, leukemias, autoimmune disorders, Systemic Lupus Erythematosus (SLE), immune synapse

Granted patents or published applications

The international application published as WO 2023/129995 A3 on Jul 6, 2023.

Related scientific references

Chockley, P. et al. Synapse-tuned CARs enhance immune cell anti-tumor activity. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-022-01650-2
https://www.nature.com/articles/s41587-022-01650-2#citeas
https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/st-jude-makes-better-car-immunotherapies-using-an-anchor.html

Licensing opportunities

We are seeking partners to develop cell therapies using this new method.  

Contact the Office of Technology Licensing (Phone: 901-595-2342, Fax: 901-595-3148) for more information.