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  • br Diseases which have been treated

    2020-10-19


    Diseases which have been treated with proteins linked to HSA A number of therapeutic products conjugated to HSA have now been approved for clinical use (Table 2). For example, fatty AZD8055 derivatives of human insulin bound to HSA have applications in the treatment of diabetes while paclitaxel-HSA nanoparticles have been used to treat various cancers such as metastatic breast cancer and advanced pancreatic cancer. It has even proved possible to use HSA to deliver a bioactive gas, nitric oxide (NO), to treat ischemic/reperfusion injury, cancer, and bacterial infections. While endogenous S-nitrosated HSA occurs naturally in blood plasma and serves as a NO donor, analogues have been developed in which the HSA molecule has many conjugated SNO groups (poly-SNO-HSA). Interestingly, while SNO-HSA inhibits apoptosis, poly-SNO-HSA possesses very strong pro-apoptotic effects against tumor cells [73]. Albiglutide, a glucagon-like peptide-1 agonist (GLP-1 agonist) for the treatment of type 2 diabetes (marketed as Tanzeum and as Eperzan and the US and Europe, respectively), was one of the first HSA-peptide or protein fusion product to be approved for clinical use. Whereas the half-life of pharmacologically active native GLP-1 is 1–2 min, albiglutide’s half-life is 4–7 days, which allows it to be administered weekly rather than more frequently [74]. IL-2, which is used in passive cancer immunotherapy, is another successful example. One of the IL-2 limitations is its low serum half-life, which necessitates high doses that have severe side-effects. To overcome these issues, Adabi et al. therefore fused IL-2 to an albumin-binding domain from streptococcal protein G. The resulting fusion protein, ABD-rIL-2, binds to serum albumin, and had a three-fold increase in its terminal half-life in serum relative to recombinant IL-2, when tested in BALB/c mice [75]. The side effects of GH therapy were reported to be rare and it was shown to have a favorable overall safety profile [76].
    Immune responses of patients towards the modified drugs
    Advantages of PEGylation and HSA fused drug PEGylation creates relatively simple changes in a protein’s structure. However, such changes can have significant effects on functions such as signaling, targeting, catalysis, and catabolism, circulation time in the blood, the degree of immunogenicity/antigenicity, body-residence time and stability. In part these effects are due to the fact that PEG shields the protein surface from degradative agents and from the immune system. Additionally, the increased hydrodynamic radius that results from PEGylation usually decreases the efficiency of kidney clearance of the protein in question [16]. The widespread acceptance of PEG conjugates can be attributed to the exceptionally favorable combination of physicochemical and biological properties of the polymer. This includes its solubility in aqueous and most organic solvents, biocompatibility, lack of toxicity and (usually) low immunogenicity [67]. The favorable properties of PEG also result in peptide and protein conjugates that are soluble and active in organic solvents and that have reduced levels of absorption to surfaces. This last property is particularly useful in the case of PEGylated liposomes and niosomes, greatly increasing their utility for drug delivery [47]. The FDA approval of several PEGylated therapeutic proteins highlights their advantages. Some of the most important advantages are their prolonged body-residence time, which allows a drug to be administered less frequently, which arises from their increased resistance to degradative agents such as proteases or nucleases, and decreases in immunogenicity. Given these advantages, it is perhaps unsurprisingly that PEGylation has allowed the creation of blockbuster products such as Pegasys (peginterferon alfa-2a) and PEG-Intron (PEG-Intron (Peginterferon alfa-2b) [16]. The unusually long circulation time of HSA (19 days) has similarly encouraged researchers to use it to prolong the serum half-lives of other proteins either through genetic fusion or by chemical conjugation. [102]. It has been known for some time that HSA’s longevity in serum is due in large part to its electrostatic repulsion in kidneys and to FcRn-mediated recycling in the endothelium. [[14], [15], [16],103], However, it was initially unclear if fusion with HSA would increase the longevity of other proteins attached to it or if this would simply result in a decrease in HSA longevity. Fortunately, subsequent investigations proved these concerns to be largely unfounded.