6. PEG Therapeutics: BMS-387032 order clinical Applications and Challenges for Development PEG-based therapeutics were initially dismissed as interesting, but impractical to be translated in clinical setups. However, a growing number of products have shown that they can satisfy the stringent requirements of regulatory authority approvals (Table 1). Clinically used PEG conjugates are described below. Table 1 PEG therapeutic systems Inhibitors,research,lifescience,medical with in the market or clinical development. 6.1. PEG-Proteins Conjugate 6.1.1. Adagen (mPEG per Adenosine Deaminase) Enzon’s Adagen was among the first few PEG-protein conjugates to enter the clinic with FDA approval in
1990 . It is used as a placement therapy to treat severe
combined immunodeficiency (SCID) disease. SCID is an autosomal recessive genetic disorder caused by adenosine deaminase deficiency. It is usually fatal in children unless the patient is kept in protective isolation or undergoes a bone marrow transplant. As an alternative, Adagen is administered intramuscularly every Inhibitors,research,lifescience,medical 7 days. It is a replacement therapy Inhibitors,research,lifescience,medical and is repeated for the rest of the life by the patients following the dosing schedule: 10Ukg−1, 15Ukg−1, and 20Ukg−1 for the first three doses, and the weekly maintenance dose of 20Ukg−1. However, immune related problems have been reported for pegademase and its long-term treatment benefits are yet to be elucidated. Also, the high cost of treatment ($200,000–$300,000 per annum per patient) is an obvious disadvantage [60–62]. 6.1.2. Oncaspar® (mPEG-L-Asparaginase) Oncaspar (pegaspargase) is an antineoplastic Inhibitors,research,lifescience,medical drug from Enzon Pharmaceuticals Ltd. and was approved by FDA in 1994. Oncaspar is a PEG-modified entity of
the enzyme L-asparaginase and is used for the treatment of acute lymphoblastic leukaemia . PEGylation was attempted to overcome several factors limiting the utility of asparaginase as therapeutic agent such as high clearance, immunologic factors such as antibodies to asparaginase owing to bacterial protein Inhibitors,research,lifescience,medical and also inactivation due to conversion to asparagine via asparagine synthetase. Also, the immunological side effects such as hypersensitivity reactions (up to 73%) were major factors that limited clinical utility of L-asparaginase Liothyronine Sodium . Pegaspargase was developed in the 1970–1980 while it was translated in the clinical trials in the 1980. Taking clues from the preclinical studies, a series of systematic clinical studies revealed the effectiveness of the pegaspargase as compared to its non-PEG-grafted parent drug [65, 66]. Clinical trials demonstrated safety in terms of fewer incidence of hypersensitivity reactions and prolonged duration of action. The trials defined different protocols (weekly or every two weeks) and recipes of multidrug regime to treat different malignancies.