Infertility affects one in seven couples worldwide, becoming a severe disease right after cancer and cardiovascular disease in terms of its harmful effect on human health. Follicle-stimulating hormone (FSH), either extracted from urine or produced by genetic engineering, has been widely used by specialists to improve fertility.
The use of human FSH (hFSH) extracted from human urine is limited by its high cost, labor-intensive collection and the difficulty in tracing urine sources as well as the potential risk of virus contamination. The recombinant hFSH is a better option as it can avoid the above problems. hFSH is a glycoprotein with a molecular weight of about 43 kilodalton (kD). As a therapeutic drug, it is necessary to maintain the correct 3-dimensional structure and glycosylation to maintain its bioactivity. The ability to perform complex post-translational modifications is a major reason that most therapeutic biologicals are produced in mammalian cell lines. Among them, the Chinese Hamster Ovary (CHO) cell system is the most common host cell system for eukaryotic gene expression. Therapeutic recombinant proteins such as EPO and G-CSF have been successfully expressed in CHO cells. These proteins can not only be folded and glycosylated properly, but also be secreted in favor of the subsequent downstream processes, such as purification.
Although the recombinant hFSH produced by CHO cells has been in the market for years, several defects still need to be solved. First, the current recombinant FSH has a short plasma half-life, thus requiring patients being administered repeatedly to achieve optimal therapeutic efficacy. For example, hFSH must be administered intramuscularly or subcutaneously as daily injection routinely for 8-12 days or more when used for ovulation induction, resulting in poor compliance. In addition, this treatment regimen is often accompanied with severe cytotoxic effects to nervous, endocrine and immune system, causing a number of frequently-occurring complications such as ovarian hyperstimulation syndrome, clinical manifestations associated with ovarian enlargement, increased vascular permeability and the formation of ascites, which can be life-threatening in severe cases. Furthermore, the production cost of the recombinant hFSH is very high due to the low level of cell expression and the intensive production process. Last but not least, hFSH is a glycosylated protein comprising an α-subunit and a β-subunit linked via non-covalent bond, and its bioactivity depends on the correct assembly of the two subunits. It remains challenging to maintain the right assembly of the two subunits during the expression and purification process of protein in order to obtain a biologically active molecule useful for therapeutic purpose until the present disclosure. To overcome the defects and insufficiency of the existing hFSH products, the present disclosure provides a new molecule of recombinant hFSH with prolonged plasma half-life, sufficient biological activity and high level of protein expression, resulting in improved pharmacokinetics and/or pharmacodynamics. Thus, a lower dosage may be used and/or better or different therapeutic efficacy with less side effects may be achieved.