Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 273

GSM-CSF

α

β

Cell membrane

Cell cytoplasm

S

S

P

Figure 10.2 The GM-CSF receptor. Ligand binding appears to promote the phosphorylation of various
cytoplasmic polypeptide substrates (at least in part via an associated JAK2), leading to signal transduction

Neutropenia is a condition characterized by a decrease in blood neutrophil count below 1.5 10 9
cells per litre; a normal blood count is (2.0-7.5)

10 9 cells per litre. Its clinical symptoms include
the occurrence of frequent and usually serious infections, often requiring hospitalization. Neutro-
penia may be caused by a number of factors (Table 10.6), at least some of which are responsive to
CSF treatment. Particularly noteworthy is neutropenia triggered by administration of chemothera-
peutic drugs to cancer patients. Chemotherapeutic agents (e.g. cyclophosphamide, doxorubicin
and methotrexate), when administered at therapeutically effective doses, often induce the destruc-
tion of stem cells and/or compromise stem cell differentiation.
Filgrastim is a recombinant human G-CSF (produced in E. coli ), approved for chemotherapy-
induced neutropenia (Table 10.2 and Box 10.1). Neulasta is the tradename given to a PEGylated
form of fi lgrastim approved for general medical use in the USA in 2002 (Table 10.2). Manufacture
of this product entails covalent attachment of an activated monomethoxypolyethylene glycol mol-
ecule to the N-terminal methionyl residue of fi lgrastim. The product is formulated in the presence
of acetate buffer, sorbitol and polysorbate and is presented in pre-fi lled syringes for s.c. injection.
As in the case of PEGylated interferons (Chapter 8), the rationale for PEGylation is to increase the
drug's plasma half-life, thereby reducing the frequency of injections required.

Table 10.6 Some causes of neutropenia

Genetic (particularly in black populations)
Severe bacterial infection
Severe sepsis
Severe viral infection
Aplastic anaemia a
Acute leukaemia
Hodgkin's/non-Hodgkin's lymphoma
Various drugs, especially anti-cancer drugs
Autoimmune neutropenia

a Aplastic anaemia describes bone marrow failure, characterized by serious
reduction in the number of stem cells present.