IgG4 Hinge Containing Chimeric Antigen Receptors Targeting Glypican-1 For Treating Solid Tumors

Abstract:

Pancreatic cancer is the fourth most common cause of cancer deaths in the U.S. The overall 5-year survival rate is 8.5%. Glypican-1 (GPC1) is a cell surface heparan sulfate proteoglycan protein overexpressed in pancreatic cancer. Due to preferential expression, GPC1 represents a potential candidate for targeted therapy for pancreatic cancer and other GPC1-expressing cancers, such as prostate.

Researchers at National Cancer Institute (NCI) developed novel Chimeric Antigen Receptors (CARs) specific for GPC1 that include short Immunoglobulin subclass 4 (IgG4) hinge sequences between the extracellular antigen recognition domain and the transmembrane domain. Hinge changes in CAR design can achieve the threshold of antigen density required for optimal CAR-T cell activity. Significantly, the optimized GPC1-IgG4 hinge CARs have shown rapid and complete tumor regression in mouse models.

Competitive Advantages:

• GPC1-targeted CAR T cells demonstrated potent antitumor efficacy in a peritoneal dissemination xenograft mouse model.
• Recombinant receptors providing both antigen-binding and T-cell–activating functions 
• Likely successful targeting and lower toxicity due to high affinity of the GPC1 nanobody fragment
• Incorporation of the IgG4 hinge sequence increases the potency of the nanobody based CARs against pancreatic cancer 
• CARs using the IgG4 hinge domain are available for immediate testing
• Potential immunotherapy for several cancer types with few treatment options – including pancreatic adenocarcinoma and uterine cervical cancer 

Commercial Applications:

• Immunotherapeutic applications for the treatment of pancreatic adenocarcinoma – a significant unmet medical need
• Immunotherapeutic applications for the treatment of several GPC1-positive malignancies – including uterine cervical cancer, colorectal cancer, liver cancer, glioma, lung cancer, head and neck cancer, thyroid cancer, endometrial cancer, breast cancer and ovarian cancer