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

Abstract:

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.