Crystallization of IGF-1

• US 7,238,658 B2
• Filed: 04/14/2005
• Issued: 07/03/2007
• Est. Priority Date: 02/09/2001
• Status: Expired due to Fees

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Ultsch, Mark, Schaffer, Michelle, Vajdos, Felix
• Primary Examiner(s): Nashed; Nashaat T.
• Application Number:
  US11/107,672
• Publication Number:
  US 20050215477A1
• Time in Patent Office: 810 Days
• Field of Search: None
• US Class Current: 514/8.6
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/65 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
• CPC Class Codes: C07K 2299/00 Coordinates from 3D structures of peptides, e.g. proteins or enzymes

Abstract

Crystalline IGF-1 is provided along with a method for production thereof. Crystallizing IGF-1 comprises the steps of mixing an aqueous solution comprising IGF-1 with a reservoir solution comprising a precipitant to form a mixture; and crystallizing the mixture, optionally also recrystallizing and isolating the crystalline IGF-1. In addition, a method for identifying IGF-1 indirect agonists is provided using a detergent as a standard for the level of inhibition of binding of IGFBP-1 or IGFBP-3 to IGF-1 and/or using the coordinates of the binding pockets of IGF-1 to which a candidate indirect agonist binds for structure-based drug design.

Claims

1. A method of treating a mammal suffering from an agonist disorder, said method comprising administering to said mammal an effective amount of a composition comprising a crystal formed by insulin-like growth factor-1 (IGF-1) of SEQ ID NO:

1 that diffracts x-ray radiation to produce a diffraction pattern representing the three-dimensional structure of the IGF-1, and has approximately the following cell constants a=31.831 Å

, b=71.055 Å

, c=65.995 Å

, and a space group of C2221₁, and α

=β

=γ

, wherein the IGF-1 is biologically active when resolubilized, wherein said agonist disorder is selected from the group consisting of hyperglycemic disorders, obesity, increased mass-to-lean ratio, heart dysfunctions, wasting, kidney disorders, lung diseases, neurological disorders, neuromuscular disorders, GH- insufficiency, whole body growth disorders, Turner'"'"'s syndrome, and immunological disorders.

2. The method of claim 1 wherein the mammal is human.

3. The method of claim 1 wherein the disorder is diabetes, obesity, a heart dysfunction, AIDS-related wasting, a kidney disorder, a neurological disorder, a whole body growth disorder, or an immunological disorder.

4. The method of claim 1 wherein the hyperglycemic disorder is selected from the group consisting of Type I diabetes, Type II diabetes, severe insulin-resistance, hyperinsulinemia, hyperlipidemia, insulin-resistant diabetes, Mendenhall'"'"'s Syndrone, Werner Syndrome, leprechaunism, lipoatrophic diabetes, and other lipoatrophies.

5. The method of claim 1 wherein the kidney disorder is selected from the group consisting of acute and chronic renal insufficiency, end-stage chronic renal failure, glomerulonephritis, interstitial nephritis, pyelonephritis, glorneruloselerosis, Kirumeistiel-Wilson Syndrome in a diabetic patient, and kidney failure after kidney transplantation.

6. The method of claim 1 wherein the immunological disorder is selected from the group consisting of immunodeficiencies, decreased CD4 counts, decreased immune tolerance, and chemotherapy-induced tissue damage.

7. The method of claim 1 wherein the neurological or neuromuscular disorder is selected from the group consisting of peripheral neuropathy, multiple sclerosis, muscular dystrophy, myotonie dystrophy, and catabolic states associated with wasting.

8. The method of claim 1 wherein the whole body growth disorder is selected from the group consisting of short stature and Laron'"'"'s syndrome.