Long Acting PEGylated Interferon Application of PEG

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Long Acting PEGylated Interferon: Application
of PEG

Since the discovery of interferon by British and Swiss scientists in 1957, the mystery of
interferon has been gradually unveiled. In 1966, scientists discovered the antiviral
mechanism, immunomodulatory and antitumor effects of interferon; in 1977, interferon
was used for the first time in the treatment of chronic hepatitis B with 2 out of 4 patients
treated showing the disappearance of HBeAg. In 1986, the U.S. FDA officially approved
interferon alpha for the treatment of malignancies and viral disorders, such as chronic
hepatitis B and hairy cell leukemia, and later approved for chronic myelogenous leukemia
(CML), follicular non-Hodgkin lymphoma (NHL), melanoma, and AIDS-related Kaposi's
sarcoma.

What Are Interferons?

Interferons (IFNs) are a group of signaling proteins secreted by host cells in
response to the virus infection. The IFNs can be subdivided into three types (types I, II,
and III) based on their different receptors.

Image source: Wikipedia

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Type I IFNs: IFN-α, IFN-β, and more. They are mainly produced by
fibroblasts and monocytes and have strong antiviral properties.

Type II IFN: IFN-γ, which is produced by T cells, and its immunomodulatory effect is
stronger than its antiviral activity.

Type III IFNs: IFN-λ1, IFN-λ2, and IFN-λ3. Like type I IFNs, they also have antiviral and
immunomodulatory functions, but their effects are different for the different receptors they
used.

Clinical Uses of Interferons

Antiviral activity

Interferon is a broad-spectrum antiviral agent that inhibits both RNA and DNA viruses. It
does not directly kill or inhibit viruses, but rather blocks their multiplication by acting on cell
surface receptors and causing the cells to produce antiviral proteins. Also, interferon can
directly activate immune cells or indirectly inhibit the replication of viruses, and then inhibit
the growth and multiplication of viruses during early viral infections in the body.

Antitumour activity

Interferon can inhibit cell division, especially for rapidly dividing cells. Its anti-tumor
mechanism includes inhibiting tumor cell proliferation, promoting tumor cell apoptosis, and
inhibiting tumor angiogenesis.

Treatment of multiple sclerosis (MS)

Multiple sclerosis is the most common immune-mediated disease affecting the central
nervous system. IFN β-1b was approved by the US Food and Drug Administration in 1993
as the first disease mitigation therapy (DMT) for the treatment of multiple sclerosis (MS).

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Immunomodulatory effect

Interferon has effects on both cellular and humoral immunity. It enhances the activity of
natural killer cells, thus acting as a regulator of immunity, and also enhances the cytotoxic
activity of macrophages and regulates the self-stabilizing function of immunity, etc.

Interferons also have antibacterial, antiparasitic, and antifibrotic effects. The table below
shows the approved therapeutic interferons in USA and EU.
Note, Besremi (ropeginterferon alfa-2b-njft), developed by Pharma Essentia and
approved by FDA on 12 Nov, 2021, is not listed in the table.

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Therapeutic interferons approved in the United States of America (USA) and European
Union (EU). Source: Reference [1]

Long-Acting PEGylated Interferons (IFNs)

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Because of the short half-life of IFNs, their clinical application are limited, and only high
and frequent doses can achieve the therapeutic effects required. The use of these drugs
has also led to frequent adverse reactions. Therefore, the modification of recombinant
human IFNs (rhIFNs) to optimize their pharmacokinetic properties has become a key way
to maximize their efficacy while reducing their adverse effects. At present, the covalent
binding of polyethylene glycol (PEG) to the protein is the most commonly used
method to prolong the half-life of IFN in serum.

The PEGylation of IFN inhibits the decomposition of proteolytic breakdown and renal
clearance, thereby prolonging its half-life, reducing the frequency of administration, and
possibly having better tolerance and compliance.

PEGylated formulations improved the pharmacological properties of unmodified IFN, such
as:
(i) improved IFN solubility and stability by reducing proteolytic degradation;
(ii) reduced renal clearance (e.g., by increasing its size above the renal cutoff of 40-50
kDa);
(iii) reduced plasma clearance (e.g. by reducing metabolic degradation and
receptor-mediated uptake of the protein from the systemic circulation);
(iv) improving the safety profile of the protein by shielding it from antigenic and
immunogenic epitopes;
(v) extending the circulation time from 5 to 90 hours, which is achieved by increasing its

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molecular size to the size required for half-life extension.
​ A key advantage of using PEGylated interferon is that patients require fewer doses to
maintain the necessary therapeutic levels in circulation (fewer doses administered), which
is achieved by improving their pharmacokinetic profile and leads to a reduced frequency
of side effects.

Several long-acting PEGylated interferons such as PegIntron® (Schering-Plough
Corporation and Sylatron, Merck), ViraferonPeg® (Merck Sharp & Dohme Corp),
Pegasys®, (Genentech-Roche), and Plegridy® (Biogen Idec), Sylatron ® (Merck &
Co.), Besremi (Pharma Essentia), envisaging to enhance their stability and blood
circulation half-life.(Find more form the article FDA Approved PEGylated drugs.)

Biochempeg provides PEG derivatives for PEGylated interferon​ and a variety of
supporting technical services. We will support you in all aspects of PEGylation from the
laboratory R&D level to the scale-up level.

References:
[1] Castro, L.S.; Lobo, G.S.; Pereira, P.; Freire, M.G.; Neves, M.C.; Pedro, A.Q. Interferon-Based
Biopharmaceuticals: Overview on the Production, Purification, and Formulation. Vaccines 2021, 9,
328. https://doi.org/10.3390/ vaccines9040328

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