Protein therapeutics have gained momentum in recent years and become a pillar in treating many diseases and the only choice in several ailments. Protein therapeutics are highly specific, tunable, and less toxic than conventional small drug molecules. However, reaping the full benefits of therapeutic proteins in the clinics is often hindered by issues of immunogenicity and short half-life due essentially to fast renal clearance and enzymatic degradation. Advances in polymer chemistry and protein engineering allowed overcoming some of these limitations. Strategies to prolong the half-life of proteins rely on increasing their size and stability and/or fusing them to endogenous proteins (albumin, Fc fragment of antibody) to hijack physiological pathways involved in protein recycling. On the downside, these modifications might alter therapeutic proteins structure and function. Therefore, a compromise between half-life and activity is sought. This review covers half-life extension strategies using natural and synthetic polymers as well as fusion to other proteins and sheds light on genetic engineering strategies and chemical and enzymatic reactions to achieve this goal. Promising strategies and successful applications in the clinics are highlighted. DOI: . /adfm.functions that cannot be mimicked by simple chemical compounds. Since the action of proteins is highly specific, they barely interfere with normal biological processes and cause less adverse events. Protein therapeutics are frequently derived from proteins naturally produced by the body. These agents are therefore often well tolerated and poorly immunogenic. However, proteins also suffer from significant limitations. Proteins with a molecular weight below the threshold for kidney filtration ( kDa, the size of human serum albumin) are cleared from the systemic circulation within a day. Many proteins are even cleared within a few hours or a few minutes when metabolism contributes to elimination. Therefore, therapeutic proteins need to be injected to patients several times a week (e.g., erythropoietin) or even several times a day (e.g., glucagon-like peptide-or GLP-), resulting in peaks and valleys in plasma concentrations with the alternate risks of systemic side effects and suboptimal therapeutic concentrations. Moreover, frequent administration of medication causes patient discomfort and reduces quality of life. A second limitation of proteins lies in protein immunogenicity. Foreign proteins from prokaryotes or animals might present interesting therapeutic properties in humans. However, intrinsic immunogenicity of nonhuman proteins hampers their therapeutic use in the clinic because specific antibodies generated against the foreign protein neutralize its activity and result in a loss of therapeutic efficacy over time. The unwanted immune response might even cause more serious general immune effects such as anaphylaxis.Over the last three decades, protein engineering has largely demonstrated that it can provide solutions to the limitations of natural proteins. B...
