University of Pittsburgh researchers have identified a novel extracellular protein domain in hepatocellular carcinoma (HCC) and developed a monoclonal antibody (mAb) to recognize this target. These novel antibodies have the potential to selectively bind to these proteins, disrupting key cellular processes and leading to cell growth arrest.
Description
HCC is one of the most lethal human cancers, often diagnosed in an advanced stage and accounts for 90% of primary liver cancer cases. Current treatment options are limited and remain an unmet clinical need. The most oncogenic fusion gene in HCC cells, MAN2A1-FER, has been identified. This gene fusion has been shown to ectopically phosphorylate the extracellular domains of transmembrane proteins PDGFRA, MET, AXL, and N-cadherin initiating downstream processes promoting cell growth. A novel antibody that binds to the extracellular domain of PDGFRA with high affinity and specificity has the potential to be a novel approach to the treatment of HCC through drug-conjugated/radio-labelled antibodies of CAR T cell therapy.
Applications
• Hepatocellular carcinoma
• Prostate cancer
• Glioblastroma multiforme
Advantages
HCC is often diagnosed when patients are in the late stage of the disease and unable to benefit from therapies used to treat early-stage liver cancer patients, liver transplant or resection. Even in early-stage HCC, the lack of transplantable livers can hinder the treatment of patients. Safe and effective therapies for HCC could substantially improve patient outcomes. In this novel approach, a mAb has been developed to selectively disrupt processes in HCC cells and other MAN21A-FER containing cells including prostate, breast, and glioblastoma cancers. This selective targeting of MAN21A-FER containing cells could reduce the risk of side-effects from small molecule treatments which are often systemically administered.
Invention Readiness
A panel of mouse mAbs have been developed and found to bind to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The antibody 2-3B-G8 selectively deactivated cell growth signaling pathways in the MAN2A1-FER positive cancer cells HUH7 and led to a large number of cell deaths in other MAN2A1-FER positive cancer cells, including HUH7 and HEPG, with no impact on MAN2A1-FER negative cells. In vivo studies in mice xenografted with HEPG2 of HUH7 cells revealed treatment with Monomethyl auristatin E conjugated to 2-3B-G8 slowed tumor growth, eliminated metastasis, and significantly reduced mortality compared to controls.
IP Status
Patent Pending
