Half-Life Extension of Biopharmaceuticals
by Michael Pennington
Biopharmaceuticals have emerged as important drugs since the first approval of recombinant insulin by the FDA in 1982 (Eli Lilly’s Humulin). The vast majority of biopharmaceuticals on the market today are based upon endogenous peptides and proteins including: enzymes, hormones, growth factors, interferons and antibodies. These molecules possess superior drug properties owing to the fact that they are naturally selective recptor binding/activating ligands. This typically lowers the amount of off-target side effects, which improve their drug safety profile. The primary obstacle in developing one of these biopharmaceuticals is they usually have very short half-lives due to proteolytic degradation and/or rapid renal clearance.
Witteloostuijn, Pederson and Jensen (doi: 10.1002/cmdc.201600374) have completed a very thorough review of the chemical modification procedures related to half-life published in ChemMed Reviews (requires subscription). This review covers all of the key methods including pegylation, peg-like mimetics, dextran conjugation (including multiple different sugar derivatives) and lipidation. Recent improvements such as conjugation to bile acids, perfluoralkylation and bipyridylation are also described. For researchers involved in developing peptide or protein-based therapeutics, you will find this review to be extremely useful.