Summary of the technology
A novel Recombinant leptin mutant acts as antagonist has a strong potential for pharmacologic agent for autoimmune and inflammatory diseases, cancers, and cardiovascular disease, among others. Substitution of two to four amino acid residues of leptin to alanine converts agonist to antagonist without reducing affinity toward leptin receptor.
Keywords: Leptin, antagonist, mutein, multiple sclerosis, inflammatory bowel syndrome, rheumatoid arthritis, fibrosis, cardiovascular disease, breast cancer, colon cancer, prostate cancer, ovarian cancer, obesity
Project ID : 8-2006-198
Description of the technology
Superactive High Afinity Leptin antagonist, mutein, multiple sclerosis, inflammatory bowel syndrome, rheumatoid arthritis, fibrosis, cardiovascular disease, CKD Cachexia, Osteoarthritis
(1) In vivo tests in animal (mouse) models, (2) Preparation of second generation of antagonists with increased affinity toward leptin receptor and longer in vivo persistence in circulation
Patent number application: WO2011/132189A3
- Advances treatment of many diseases by blocking undesired leptin effects
- Interacts with mammalian leptin receptor with affinity identical to non-mutated leptins
- Can be easily prepared in large quantities as recombinant protein expressed in E. coli
- Effectiveness established in three mice models of human acute and chronic fibrosis
- Recombinant leptin mutein acts as antagonist
- Isolated DNA molecule encoding super active leptin antagonist
- Strong potential for pharmacologic agent for CKD (Chronic Kidney Disease) associated cachexia, autoimmune and inflammatory diseases, cancers, and cardiovascular disease, among others
- Substitution of two to four amino acid residues of leptin to alanine converts agonist to antagonist without reducing affinity toward leptin receptor
- Addresses multiple markets for treatment of multiple disease entities, specifically, CKD associated cachexia
- Expands various research fields stressing proteins that inhibit leptin activity
- Testing super activeleptin antagonist activity in additional in vivo models e.g., Cachexia Inflammatory Bowel Disease in mice or others
- Preparation of leptin antagonists with more potent activity in vivo
- A. Gertler. Development of leptin antagonists and their potential use in experimental biology and medicine. Review. Trends in Endcrinol. Metab. 17: 372-8 (2006).
- Elinav E, Ali M, Bruck R, Brazowski E, Phillips A, Shapira Y, Katz M, Solomon G, Halpern Z, Gertler A.Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. Hepatology 49:278-86 (2009)
- Shpilman M, Niv-Spector L, Katz M, Varol C, Solomon G, Ayalon-Soffer M, Boder E, Halpern Z, Elinav E, Gertler A.Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem. 286:4429-42 (2011).
- Gertler A, Elinav E.Novel superactive leptin antagonists and their potential therapeutic applications. Curr Pharm Des. 20:659-65 (2014)
- W.W. Cheung et. al A Pegylated Leptin Antagonist Ameliorates CKD-Associated Cachexia in Mice. J. Am. Soc. Nephrol 25:119-282 (2014).