Neutropenia, a common adverse event related to chemotherapy, characterised by abnormally low levels of neutrophils in the blood, which play an important role in the immune response. Consequently, neutropenia increases the risk of serious infections during treatment in patients with cancer.
Currently, granulocyte colony-stimulating factor (G-CSF) is the most common drug for the prevention and treatment of chemotherapy-induced neutropenia. Commonly used drugs include recombinant human granulocyte colony stimulating factor (rhG-CSF) and PEGylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF).
rhG-CSF & PEGylated rhG-CSF
G-CSF belongs to the hematopoietic growth factor family which plays a crucial role in the proliferation, differentiation, and maturation of committed progenitor cells to granulocytes, such as neutrophils.
The main mechanism of action of G-CSF is:
- a. specifically acting on precursor cells of myeloid granulocyte and macrophage to promote differentiation and proliferation of the precursor cells to mature granulocyte;
- b. acting on bone marrow mature neutrophils to promote release from bone marrow to peripheral blood;
- c. activating the function of mature granulocytes, enhancing their ability of migration, phagocytic and bactericidal, and prolonging their survival time;
- d. stimulating the release of bone marrow hematopoietic stem cells to peripheral blood.
rhG-CSF is a humanized formulation of G-CSF synthesized through bioengineering technology, which is mainly used for neutropenia after antitumor therapy, and is an important supportive therapy for cancer patients. rhG-CSF is used to reduce the incidence, duration, and severity of febrile neutropenia, and thus ensures that the antitumor therapy is completed in a timely manner and in sufficient quantity. However, rhG-CSF has a short half-life (only about 3.5 hours), resulting in frequent injection and low patient compliance.
To overcome these problems, long-acting technologies such as PEGylation have been used for the development of long-acting rhG-CSF. PEG-rhG-CSF is a protein formed by covalently binding polyethylene glycol (PEG) at the N-terminal end of the amino acid sequence of rhG-CSF. PEGylation can shield the antigenic determinants on the surface of rhG-CSF from being recognized and cleared by the immune system, so that it has reduced antigenicity and immunogenicity, and is less likely to produce neutralizing antibodies. Meanwhile, the relative molecular weight of rhG-CSF after PEGylation is greatly increased, which is not easy to be filtered by glomerulus, significantly prolonging the half-life in vivo.
Note: PEGylation, a promising technology developed in the late 1970s, couples active PEGs with short-acting drugs, where the spatial structure of the drug molecule is affected and the biochemical properties are altered so that the drug achieves the effect of increased half-life, increased aqueous solubility, decreased immunogenicity, improved pharmacodynamic properties and pharmacokinetics, and expanded clinical applications. Biopharma PEG provides PEG derivatives for PEGylated long-acting G-CSF and various technical services. If you have any requests, please feel free to contact us at firstname.lastname@example.org.
rhG-CSF Drugs Market Size
In the 1970s, scientists from Japan and the U.S. began to engage in basic research related to G-CSF, and in 1985, the gene sequence of G-CSF was identified. In February 1991, the first rhG-CSF, filgrastin (NEUPOGEN®), was approved by the FDA in the U.S., and marketed in the U.S. as a first-generation short-acting G-CSF.
In January 2002, the first PEG-rhG-CSF Pegfilgrastim (Neulasta®) was approved by the FDA in the U.S. as a second-generation, long-acting G-CSF. In 2003, the annual sales of Neulasta reached US$1.3 billion, and in 2016 reached a peak of US$4.715 billion. However, with the expiration of patents in Europe and the United States and the launch of biosimilars, sales of Neulasta were only $2.293 billion in 2020.
According to IQVIA, the global market share of G-CSF is $6.02 billion in 2022, dominated by Neulasta. In addition to Neulasta, the original product of Amgen, there are several biosimilars listed in the U.S., namely Fulphila, Udenyca, Ziextenzo, Nyvepria, Fylnetra and others.
 Tiwari D, Haque S, Jawed A, Mishra MK, Govender T, Kruger HG. Efficient Purification of rhG-CSF and its PEGylated Forms and Evaluation for In Vitro Activities. Protein Pept Lett. 2015;22(10):877-884. doi:10.2174/0929866522666150728115146
 Ba Y, Shi Y, Jiang W, Feng J, Cheng Y, Xiao L, Zhang Q, Qiu W, Xu B, Xu R, Shen B, Luo Z, Xie X, Chang J, Wang M, Li Y, Shuang Y, Niu Z, Liu B, Zhang J, Zhang L, Yao H, Xie C, Huang H, Liao W, Chen G, Zhang X, An H, Deng Y, Gong P, Xiong J, Yao Q, An X, Chen C, Shi Y, Wang J, Wang X, Wang Z, Xing P, Yang S, Zhou C. Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association. Cancer Biol Med. 2020 Nov 15;17(4):896-909. doi: 10.20892/j.issn.2095-3941.2020.0069. Epub 2020 Dec 15. PMID: 33299642; PMCID: PMC7721096.