Therapeutic hormones - Pharmaceutical Biotechnology: Concepts and Aapplications

Biomedical Engineering Reference

In-Depth Information

which refl ects overstimulation of both osteoclasts (promote bone resorption, i.e. degradation of old

bone) and osteoblasts (promotes synthesis of new bone).

In most mammals, calcitonin is synthesized by specialized parafollicular cells in the thyroid.

In sub-mammalian species, it is synthesized by specialized anatomical structures known as ulti-

mobranchial bodies.

Calcitonin produced by virtually all species is a single-chain 32 amino acid residue polypep-

tide, displaying a molecular mass in the region of 3500 Da. Salmon calcitonin differs in sequence

from the human hormone by nine amino acid residues. It is noteworthy, however, as it is approxi-

mately 100-fold more potent than the native hormone in humans. The higher potency appears due

to both a greater affi nity for the receptor and a greater resistance to degradation in vivo . As such,

salmon, as opposed to human calcitonin, is used clinically. Traditional clinical preparations were

manufactured by direct chemical synthesis, although a recombinant form of the molecule has

now gained marketing approval. The recombinant calcitonin is produced in an engineered E. coli

strain. Structurally, salmon calcitonin displays C-terminal amidation. A C-terminal amide group

(!CONH 2 ) replacing the usual carboxyl group is a characteristic feature of many polypeptide

hormones. If present, it is usually required for full biological activity/stability. As E. coli cannot

carry out post-translational modifi cations, the amidation of the recombinant calcitonin is carried

out in vitro using an α-amidating enzyme, which is itself produced by recombinant means in an

engineered CHO cell line. The purifi ed, amidated fi nished product is formulated in an acetate

buffer and fi lled into glass ampoules. The (liquid) product exhibits a shelf life of 2 years when

stored at 2-8

C.

11.8 Conclusion

Several hormone preparations have a long history of use as therapeutic agents. In virtually all

instances they are administered simply to compensate for lower than normal endogenous produc-

tion of the hormone in question. Since it fi rst became medically available, insulin has saved or

prolonged the lives of millions of diabetics. Gonadotrophins have allowed tens, if not hundreds, of

thousands of sub-fertile individuals to conceive. GH has improved the quality of life of thousands

of people of short stature. Most such hormones were in medical use prior to the advent of ge-

netic engineering. Recombinant hormonal preparations, however, are now gaining greater favour,

mainly on safety grounds. Hormone therapy will remain a central therapeutic tool for clinicians

for many years to come.