Description of Invention:
The glycoprotein hormones, which include thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and chorionic gonadotropin, are involved in the development and regulation of the ovary, testes, and thyroid. These hormones are heterodimers, each consisting of a non-covalently linked alpha and beta subunit. While the amino acid sequence of the beta subunit is hormone-specific, that of the alpha subunit is identical in all hormones within the same species. Embodied in the current invention are human glycoprotein hormones which contain specific amino acid substitutions within the alpha as well as beta subunits. These substitutions result in glycoprotein hormone analogs, or "superagonists," which exhibit a significant increase in in vitro and in vivo bioactivity over the wild-type hormone. These superagonists, therefore, appear to represent potential agents for use in the treatment of a variety of conditions, including various forms of male and female infertility and thyroid carcinoma.
Potential Area of Application:
We report here the design of superactive analogs of glycoprotein hormones with potential use in ovulatory dysfunction, luteal phase defect, unexplained infertility, male factor infertility, time-limited conception, assisted reproduction and thyroid carcinoma. The use of such analogs may not be limited to enhancement of classical actions of glycoprotein hormones in their respective target organs, but might be extended to their potential use as antineoplastic and antiviral agents.
Main Advantage of Invention:
These are the first superactive analogs developed for glycoprotein hormones with therapeutic applications for both thyroid and reproductive disorders. Selective reconstitution or addition of certain critical charged residues present in nonhominoid hormones provides a rational strategy for design of superactive analogs.
Stage of Development:
The most active hTSH mutants resulted in 100-fold higher potency and 2-fold increase in efficacy (Vmax). The multiple mutations of only alpha-subunit in hCG resulted in 5-fold higher potency and 2-fold higher efficacy.
Further Development Required:
Combined changes in the alpha and beta subunits of glycoprotein hormones may result in further optimization of potency and efficacy of the analogs. Pharmacological properties of such analogs can be also optimized according to specific therapeutic requirements by modifications of their plasma half-life.
Inventors:
MW Szkudlinski BD Weintraub M Grossman (NIDDK)
Patent Status:
DHHS Reference No. E-015-96/0 filed 08 May 1996
Serial No. 09/185,408 filed 03 Nov 1998
Relevant Publication:
* MW Szkudlinski, NG Teh, M Grossmann, JE Tropea, BD Weintraub: "Engineering glycoprotein hormone superactive analogues," Nature Biotechnology 14, 1257-1263, 1996
* MW Szkudlinski, M Grossmann, BD Weintraub: "Structure-function studies of human TSH: New advances in design of glycoprotein hormone analogs," Trends Endocrinol Metab 7, 277-286, 1996
For Additional Information Please Contact: Tara L. Kirby Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301)435-4426
Email: tarak@mail.nih.gov
Fax: (301)402-0220
