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PEG Derivatives for Long Acting rhG-CSF

Release time:2024/5/11 15:43:38

G-CSFs have become the major therapeutic option for the treatment of patients with neutropenia.

Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. It helps neutrophil replenishment more rapidly available and thus shortening the neutropenia phase.

About 90% of cancer patients experience adverse reactions such as neutropenia after radiotherapy and chemotherapy, which weaken the body's resistance, significantly increase susceptibility, and in some cases, lead to life-threatening severe infections. This also affects the chemotherapy cycle and becomes a major obstacle for patients to complete treatment. G-CSF can stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils.

Figure 1. Mechanism of G-CSF

Types and characteristics of G-CSFs

Clinically, G-CSFs are commonly divided into two types based on the duration of action: short-acting G-CSF and long-acting G-CSF.

1. Short-acting G-CSF (rhG-CSF)

Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) possesses the same biological activity and amino acid sequence as natural G-CSF and is manufactured by recombinant DNA technology using Escherichia coli implanted with the human G-CSF gene. rhG-CSF is inexpensive and has been used clinically for a long time. However, its efficacy duration is short, requiring daily intravenous or subcutaneous injection, which increases the risk of infection at the injection site and reduces tolerance, causing inconvenience in clinical application.

Filgrastim (Neupogen), a rhG-CSF developed by Amgen, is the world's first rhG-CSF used for hematopoietic progenitor cell (HPC) mobilization. It was approved for marketing in the United States in February 1991 and is currently approved for the treatment of various conditions such as bone marrow suppression, severe chronic neutropenia, acute leukemia, and aplastic anemia in more than 70 countries. Filgrastim has a short half-life (between 3.5 and 3.8 h on average).

2. Long-acting G-CSF(PEG-rhG-CSF)

PEG-rhG-CSF is a long-acting formulation obtained by conjugation rhG-CSF with polyethylene glycol (PEG). PEG-rhG-CSF has a longer duration of action  (between 45.7 and 90 h on average), requiring only one injection per course of treatment, significantly reducing the pain and inconvenience caused by frequent injections to patients, and easing their burden.

Pegfilgrastim (Neulasta®) is a PEGylated version of the second-generation rhG-CSF. In this formulation, a single 20-kDa PEG molecule is covalently attached to the recombinant N-terminal methionine (r-met) residue of rhG-CSF, which is the active ingredient in Neupogen (Filgrastim). Structurally, each ethylene oxide of PEG can combine with two or three water particles, increasing its water solubility (more hydrophilic) and hydrodynamic radius. As a result, the size of the molecule increases to approximately 38.8 kDa, leading to reduced renal clearance. Additionally, the PEG technology provides a hydrophilic protective layer that shields the proteins from immunological recognition and proteolysis.

rhG-CSF Structure.jpg
Figure 2. rhG-CSF & PEG-rhG-CSF

Currently, PEG-rhG-CSF utilizes both linear PEG and branched PEG structures for modification. Traditional PEG-rhG-CSF employs linear PEG, while 珮金®(拓培非格司亭注射液)utilizes a more stable novel PEG structure (40 kDa Y-shaped PEG). (see Figure 3). Compared to linear PEG, branched PEG structures have larger molecular weights, more complex molecular structures, and occupy larger spatial volumes. Consequently, 珮金®(拓培非格司亭注射液)has a higher degree of PEGylation, leading to greater drug stability and longer duration of efficacy.

Figure 3. The linear and Y-Shaped PEGs

Huateng Pharma can provide both linear and branched PEG derivatives for long acting PEGylated rhG-CSF. Free feel to contact us for any requirements.  

Theyab A, Alsharif KF, Alzahrani KJ, Oyouni AAA, Hawsawi YM, Algahtani M, Alghamdi S, Alshammary AF. New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy. Front Oncol. 2023 Jan 5;12:1026377. doi: 10.3389/fonc.2022.1026377. PMID: 36686781; PMCID: PMC9850083.