PEG G-CSF With Prolonged Biological Activity

Human granulocyte colony-stimulating factor (GCSF) is a 19 kDa cytokine that is approved by the US FDA for the treatment of neutropenia patients due to its ability to control the production, differentiation and function of granulocytes. The recombinant human G-CSF (rhG-CSF) was first listed in 1992 and is clinically suitable for:

1. Promote the increase of neutrophil count during bone marrow transplantation.
2. Prevent or shorten neutropenia caused by anti-tumor chemotherapy drugs: solid tumors; acute lymphoblastic leukemia.
3. Neutropenia of myelodysplastic syndrome.
4. Neutropenia of aplastic anemia.
5. Congenital and primary neutropenia.
6. Neutropenia secondary to immunosuppressive therapy (kidney transplantation).

GCSF
Image source: wikipedia.com

Although GCSF is an effective treatment for the patients, the protein has a short circulating half-life, 3.5–3.8 h, which necessitates daily injections and is fiscally burdensome. To prolong the in vivo half-life of the GCSF, Several approaches have been employed to increase the serum half-life of recombinant huG-CSF. These include conjugation with polyethylene glycol (PEG), known as PEGylation, conjugation with the sialic acid, attachment with the human serum albumin, dimerization of G-CSF, a fusion of G-CSF with Fc Domain, circularization of G-CSF, conjugation with transferrin, etc., However, PEGylation has emerged as the method of choice to increase serum half-life and reduce G-CSF's immunogenicity.

PEG is a polymer of ethylene oxide with some unique physicochemical properties. PEG has both hydrophobicity and hydrophilicity and tends to occupy a large volume in an aqueous environment by the chain flexibility and extensive hydration. Also, it shows inertness and acceptable toxicological characteristics. PEG G-CSF has significantly improved serum half-life (up to 42 h) and is thus administered once-per-cycle of chemotherapy compared to the daily dose of G-CSF. Given these benefits, in 2002, the FDA approved the administration of PEGylated rhG-CSF - PEG-filgrastim (Neulasta) as a prophylactic and therapeutic drug. Now, there are 5 PEGylated G-CSF approved by FDA.

Advantages of PEGylated rhG-CSF

1. PEGylation increases the serum half-life of therapeutic proteins primarily through increasing hydrodynamic radii and thereby reducing renal clearance.
2. Besides, PEGylation also masks the protein's surface to protect it from proteases, antibodies, and antigen processing cells, thus increasing half-life.
3. Furthermore, PEG imparts favorable attributes on the polypeptides to improve their biological distribution and solubility.

PEGylation for Drug Development

Long-acting is one of the main directions for improving the efficacy of PEGylated drugs. The advent of long-acting recombinant protein has reduced the patient's administration frequency from once a day or even multiple times to once a week, greatly reducing the physical and mental pain caused by frequent injections, and also improving patient compliance to a certain extent. At the same time, safety problems such as secondary pollution due to frequent administration can be avoided, and the treatment burden on patients can be reduced from a long-term perspective. Therefore, PEGylated long-acting drugs are easily recognized by patients and achieve a good market response.

Biochempeg, as a professional PEG supplier, provides PEG derivatives and various supporting technical services required for PEGylation of long-acting G-CSF.