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Pegylated Proteins In Anti Cancer Therapy .pdf


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Pegylated Proteins In Anti-Cancer Therapy
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.

Image source: https://www.sciencedirect.com/

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.

Image source: https://www.sciencedirect.com/

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.

Image source: https://www.sciencedirect.com/

Related Aricles:
PEGylation of Small Molecule Drugs
FDA Approved PEGylated Drugs 2020
PEGylation of Therapeutic Proteins: Development and Challange
Things About PEGylation Technology and Biopharmaceuticals You Should
Know
Potential Limitations of PEGylated Therapeutic Proteins


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