Targeting Cancer with a Novel Humanized ROR1 x CD3 DART Molecule: A Promising Therapeutic Approach for Solid and Liquid Tumors

The ROR1 protein is commonly found in various cancers but not in healthy white blood cells, making it a potential target for cancer therapy. Researchers have created a DART protein that can bind to ROR1 on cancer cells and CD3 on T cells, aiming to destroy the tumor cells. This engineered protein was modified to improve its longevity and lacks effector functions.

The protein was produced in CHO cells and purified using standard methods. Its ability to bind to both ROR1 and CD3 was tested using ELISA and SPR. The protein's effectiveness was evaluated in vitro using lymphoma and solid tumor cell lines and primary human T cells. Further, its ability to inhibit tumor growth was tested in mice models implanted with human T cells and cancer cells, followed by treatment with the DART protein via intravenous injection. The protein's activity was also assessed in mice with human PBMCs and established tumor xenografts after intravenous treatment.

The results showed that the DART protein binds specifically to ROR1 and CD3 antigens, and it can induce the lysis of ROR1-positive cancer cells in a dose-dependent manner. The protein also promoted T-cell activation and cytokine release in response to target cells. Importantly, it did not show activity without target cells and did not release cytokines with PBMCs alone. The DART protein demonstrated an extended half-life in mice with human Fc receptors. In mouse studies, the growth of certain cancer cells was inhibited by the DART protein at low doses. Additionally, the molecule showed high rates of complete response in mice with established cancer cell xenografts.

The findings suggest that the DART molecule has potential as a cancer treatment and warrants further research. The study was presented at the 107th Annual Meeting of the American Association for Cancer Research by Bhaswati Barat and colleagues, detailing the development of a humanized ROR1 x CD3 bispecific DART molecule for treating various types of tumors.