Release date:2020/4/22 11:16:11
PEGylation has been used in FDA-approved drug therapies and has achieved a successful track record. In 1990, the first PEGylated drug appeared, called Adagen, for the treatment of severe adenosine deaminase (ADA) deficiency with immunodeficiency disease (SCID). Since then, 17 PEGylated drug therapies have been approved by the FDA and sold on the market. These longer-acting solutions reduce the frequency of drug use and the dosage.

Protein therapeutics and protein engineering are one of the newest and most promising biopharmaceutical therapy approaches. Because of their high specificity and fast onset, they are the first choice for synthetic therapeutics. Currently, some biologic drugs cannot fully realize their potential due to short half-life, protein degradation, and other characteristics that interfere with pharmacokinetics (PK). Through protein PEGylation, these biomolecules can have an extended half-life in the body and can prevent from rapid renal filtration via the kidneys. Compared with unmodified forms of biomolecules, PEGylation can confer many notable and unique pharmacological advantages, such as increased drug solubility, reduced dosage frequency, toxicity and renal clearance, extended cycle life, and increased drug stability, enhanced protection against proteolytic degradation, reduced immunogenicity and antigenicity, and minimal loss of biological activity.

As more and more PEG conjugates enter advanced clinical trials, people have recognized the importance of PEGylated peptides and proteins for anti-cancer therapy. Enzymes, monoclonal antibodies and cytokines are the three main types of proteins used in anti-cancer therapy or adjuvant therapy.

1. PEGylated Monoclonal Antibody Fragment

In the field of anti-cancer therapy, monoclonal antibodies represent the main category of protein therapeutics. Antibodies work by binding to specific antigens/cell surface receptors. The fragment antigen binding (Fab ') area on the antibody can ensure this task. Depending on the receptor and receptor binding site on which the antibody is designed, it can activate cell signaling pathways that lead to apoptosis and cell growth arrest, or block cell growth pathways that ultimately lead to tumor cell death (apoptosis). The main drawback associated with antibody fragments of Fab is its short serum half-life because it lacks the Fc region of antibodies, thereby limiting its potential as a therapeutic agent. Therefore, considering the extension of serum half-life, appropriate PEGylation methods and PEG are used to ensure a minimum loss of antibody-antigen/cell surface receptor interaction. According to reports, the hinge region cysteine residue on the immunoglobulin G (IgG antibody isotype) Fab 'antibody fragment can tolerate the attachment of one or two PEG moieties (maximum molecular weight is 40 kDa) with little effect on antigen binding affinity. Compared with parent IgG, this process can also significantly increase the half-life of circulating plasma antibodies by reducing glomerular filtration and reducing immunogenicity.

 PEGylated Monoclonal Antibody Fragment

2. PEGylated Cytokines

Cytokines represent another type of protein therapeutics, mainly used as adjuvant therapy in classic anti-cancer chemotherapy protocols to control or improve the patient's condition. These small secreted proteins belong to the category of immunotherapy, which can mobilize the body's immune system to fight cancer.


PEGylated Cytokines

3. PEGylated Enzymes In Anti-Cancer Therapy

Therapeutic enzymes represent more and more biological drugs, and PEGylation has played an important role in improving some of these products. Many depleting enzymes are active against tumors. The inherent properties of enzymes to degrade amino acids are essential for the presence of cancer cells. The fate of tumor cells depends on different cellular pathways regulated by degraded substrates (amino acids). Normal cells are not affected because normal cells can synthesize the amino acids needed for their growth. This situation is especially the most advantageous aspect of using depleted enzymes in cancer treatment. Therefore, in the PEGylation process, these enzymes should be used in combination with low molecular weight (5-10kkDa) PEG and random amine binding strategies.

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