IgG4 Hinge Containing Nanobody-based CARs Targeting GPC3 for Treating Liver Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Globally, HCC is the sixth most prevalent cancer and third leading cause of cancer-related morbidity. Standard treatment for HCC is not suitable for a large proportion of liver cancer patients. Part of this is because less than a quarter of HCC patients are surgical candidates for curative-intent treatment. As a result, alternative treatments are needed. Chimeric antigen receptor (CAR) T cell therapy is a promising alternative approach selectively targets targeting tumors via tumor-specific antigens. However, to date, no effective CAR T cell therapy exists for HCC.

Researchers at National Cancer Institute (NCI) developed novel Chimeric Antigen Receptors (CARs) specific for glypican-3 (GPC3) that include short Immunoglobulin subclass 4 (IgG4) and CD28 based hinge domains and the HN3 human single-domain antibody (also called nanobody). The specific HN3 nanobody-IgG4H-CD28TM CAR included in this invention was much more potent both in in vitro cell models and in vivo mouse models.

Researchers at the NCI seek licensing and/or co-development research collaborations for developing new nanobody-based CAR and/or antibody-T-cell receptor therapies for treating liver cancer.

Competitive Advantages:

• Increased therapeutic effectiveness of CAR T therapies for the vast majority patients with HCC without impactful treatment options
• New nanobody-based CAR immunotherapy in preclinical in vivo studies has a greater decrease in tumor size compared with other CAR formats
• Nanobodies’ lack of a light chain, making them much smaller and more flexible than standard antibodies, allows: (1) binding in different modes than typical antibodies, (2) coverage of more chemical space and (3) binding to epitopes otherwise inaccessible.  
• Nanobodies can be readily genetically engineered for additional functionality and, consequently, paths to market.  

Commercial Applications:

• Treatment of liver cancer, whose worldwide incidence is increasing in direct relation to the spread of hepatitis C virus infection.
• Chimeric antigen receptor (CAR) and/or antibody-T-cell receptor cancer therapies.