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  • br Introduction Proteins therapeutic can be defined as prote

    2021-04-02


    Introduction Proteins therapeutic can be defined as proteins that are either naturally produced in the body or created in the laboratory and introduced into the patient with the aim of improving or curing a pathological condition. They are usually acquired from either microbial AF 12198 receptor or by genetically modifying an animal or plant, and their uses range from oncology to inflammation to infectious diseases [1]. Proteins therapeutic also have the advantage that they function naturally as either pharmacokinetic or pharmacodynamic drugs, as they usually serve to replace an absent protein, and the body responds as if the protein is naturally occurring [2]. Proteins often have multiple highly specific and complex functions that cannot be mimicked by simple chemical compounds. However, in common with small-molecule drugs, there are three major parameters influence their therapeutic efficacy: time (t1/2 or half-life), toxicity and targeted binding [3]. The body produces many diverse proteins that are used as therapeutics. In the case of diseases caused by the mutation or deletion of a protein-coding gene, the protein therapeutic generally replaces the abnormal or missing protein in question without the need to go through gene therapy. Protein therapeutics have multiple advantages over small-molecule drugs. In particular, the clinical development and approval time of protein therapeutics by national drug approval agencies such as the Food and Drug Administration (FDA) is generally faster than that of small-molecule drugs [1]. Protein therapeutics are categorized as having either an enzymatic or regulatory activity. They can have specifications based on their pharmacological activity, in which they replace a protein that is deficient or abnormal. Alternatively, they can augment an existing pathway, provide a novel function or activity; interfere with a molecule or organism; or deliver other compounds (including other proteins), such as a radionuclide, cytotoxic drug, or effector protein [4]. The first promoted recombinant therapeutic protein was human insulin (Humulin R) which was first produced in 1982 and has become one of the best-selling biologics worldwide after FDA approval [5]. There are now multiple approved protein therapeutics, and many of these proteins have molecular mass below 50 kDa and a short terminal half-life in the range of minutes to hours [6]. These limitations have led to the development and implementation of half-life extension approaches to lengthen the time that these recombinant proteins remain in the blood and to improve their pharmacokinetic properties as well [7]. To achieve therapeutically effective concentration over a prolonged period of time, the drug is typically applied at a local region or subcutaneously so that it is only slowly absorbed into the bloodstream. Thus, factors such as the clearance rate, volume of circulation and the bioavailability of the therapeutic drug all influence its effective half-life [7].
    The need for modified therapeutic proteins and why they need to last longer in the body Chemical and structural changes in therapeutic proteins are possible and are carried out frequently to accomplish pharmacological or clinical benefit. Such modifications are essential as the drug needs to pass through various membrane barriers, e.g. to reach a tumor. Active targeting of a drug is typically achieved by conjugating it to a target entity that improves bioavailability and reduces systemic toxicity [8]. Modified therapeutic proteins can also be applied in a technique called the Antibody Directed Enzyme Prodrug Therapy (ADEPT) for cancer targeted therapy. ADEPT therapies are designed to generate toxic chemotherapeutics at the site of malignancy, potentially improving efficacy and reducing side effects [9,10]. The design of the modified therapeutic proteins aims to produce enzyme variants with good catalytic efficiency, high-levels of stability and reduced immunogenicity. Such extra features will often increase the protein’s circulatory half-life, i.e. the time that the protein will circulate in the blood. This lead to the decrease of the number of doses required to be given to the patient, thereby reducing the possibility that the patient will generate antibodies to the modified protein and limiting the time available for the targeted cancer cells to mutate and hence avoid or resist the treatment as in case of glucarpidase. It has been shown that protein modification using PEGylation or HSA gene fusion of glucarpidase produces forms of the enzyme with a much longer half-life and more resistant to proteases [11].