ADI-PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI-PEG 20. It is a novel protein therapeutic that has demonstrated anti-tumor activity and safety in clinical trials of patients with various cancers.
Normal human cells are able to synthesize arginine from metabolic precursors via the urea cycle (see image). One of the steps in this pathway involves the argininosuccinate synthase (ASS) catalyzed conversion of citrulline to argininosuccinate. Some cancer cells from tumors such as melanoma, hepatocellular carcinoma, pancreatic cancer, prostate cancer, mesothelioma and others are deficient in ASS and must instead obtain arginine from the blood for growth and survival. Therefore, depleting arginine from the blood can control tumor growth and reduce tumor size without damage to normal tissue cells.
ADI is conjugated with polyethylene glycol (PEG) of 20,000 dalton molecular weight to increase the circulating half-life and decrease antigenicity of ADI. Similar PEGylation technology has been used with microbially-derived therapeutic proteins for systemic delivery of other anticancer drugs. Asparaginase provides a successful example of a microbial protein that, in its PEGylated form (Oncaspar®), has been used as front-line therapy against childhood leukemia for over 20 years with few serious side effects.
Conjugating ADI with PEG also allows for the drug to be administered by intramuscular (i.m.) injection which avoids possible complications known to be associated with multiple intravenous administrations. Furthermore, i.m. injections can readily be administered in an outpatient hospital setting, in a physician’s office or even in a patient’s home.
ADI-PEG 20 has been granted orphan drug status for hepatocellular carcinoma and mesothelioma in the United States and Europe. It has also been granted orphan drug status for melanoma in the United States. The FDA has offered Special Protocol Assessment in the United States and the EMEA has offered Protocol Assistance in Europe.
Broad patent protection has been obtained through a number of patents issued or pending in the United States and worldwide.