Carbohydrate-targeted optimization of therapeutic gonadotropins - Carbohydrate Chemistry: Chemical and Biological Approaches - page 461

Carbohydrate-targeted optimization of
therapeutic gonadotropins
Sandrine Donadio-Andr ´ i, Nassima El Ma ¨ , Magali Nicollo
and Catherine Ronin*
DOI: 10.1039/9781849739986-00461
Gonadotropins are a family of three glycoprotein hormones (FSH, LH and hCG) essential
for steroid production and reproductive functions. Over the past two decades, these
glycoproteins either from extractive origin or produced by recombinant technology have
been marketed for assisted reproductive techniques. Recombinant gonadotropins are
produced by rodent cell lines which display glycosylation machinery different from human
cells and often add undesired carbohydrate determinants which may alter protein folding,
induce immunogenicity and overall reduce circulatory half-life of the drug. Notably, they
fail to transfer sialic acid as N-acetylneuraminic acid (Neu5Ac) in a a 2,6-linkage as in the
natural endocrine cells and this affects their activity and duration in blood. We have
designed ST6Gal minigenes to optimize sialic acid transfer in the most common
drug-approved cell line i.e the Chinese Hamster Ovary cells. We present herein various
strategies that may be used to produce a 2,6-sialylated gonadotropins. A level of 60-90%
of sialylation may be routinely achieved depending on the enzyme minigene used to equip
the producer clone.
1 Introduction
Gonadotropins are a family of glycoproteins which includes the
mammalian hormones, Follicule-Stimulating Hormone (FSH, also
known as follitropin), Luteinizing Hormone (LH, also known as lutropin)
and chorionic gonadotropin (hCG, also known as choriogonadotropin).
These hormones are central to the complex endocrine system that
regulates normal growth, sexual development and reproductive
functions. As the mechanisms of action of these hormones became
increasingly understood, they began to be used in the management of
infertility during the early 1930's. 1 Gonadotropins have been used as
protein drugs to stimulate multiple follicle development essentially upon
the introduction of In Vitro Fertilization (IVF). 2
2 Physiology of gonadotropins
2.1 FSH
FSH stimulates steroidogenesis and gametogenesis in the gonads.
Secreted by gonadotroph cells of the anterior pituitary gland, this
hormone regulates the development, growth, pubertal maturation and
reproductive processes of the body, i.e. the menstrual cycle and ovarian
follicular maturation in women and sperm production in men. More
precisely, in males, FSH induces Sertoli cells to secrete inhibin and
stimulates the formation of Sertoli-Sertoli tight junctions. In females,