Insulin and IGF-1 receptor agonists and antagonists

• US 7,173,005 B2
• Filed: 09/24/2002
• Issued: 02/06/2007
• Est. Priority Date: 09/02/1998
• Status: Expired due to Fees

• Current Assignee: Antyra Incorporated, Novo Nordisk A/S
• Original Assignee: Antyra Incorporated, Novo Nordisk A/S
• Inventors: Fletcher, Paul, Liu, Hao, Lennick, Michael, Pillutla, Renuka, Wang, Pinger, Goldstein, Neil I., Brissette, Renee, Dedova, Olga, Blume, Arthur J., Hsiao, Ku-Chuan
• Primary Examiner(s): GROSS, CHRISTOPHER M
• Application Number:
  US10/253,493
• Publication Number:
  US 20040023887A1
• Time in Patent Office: 1,596 Days
• Field of Search: 514/12, 514/2, 514/3, 514/13, 514/17, 530/300, 530/303, 530/326, 530/330
• US Class Current: 514/8.5
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/65 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2

Abstract

Peptide sequences capable of binding to insulin and/or insulin-like growth factor receptors with either agonist or antagonist activity and identified from various peptide libraries are disclosed. This invention also identifies at least two different binding sites, which are present on insulin and insulin-like growth factor receptors, and which selectively bind the peptides of this invention. As agonists, the peptides of this invention may be useful for development as therapeutics to supplement or replace endogenous peptide hormones. The antagonist peptides may also be developed as therapeutics.

Claims

1. An insulin-like growth factor receptor antagonist comprising the Formula 2 sequence, X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃, such that X₆ and X₇ are aromatic amino acids, X₈, X₉, X₁₁, and X₁₂ are any amino acid, and X₁₀ and X₁₃ are leucine, wherein the antagonist further comprises two or more cysteines which are separated by at least 3 amino acids, with the proviso that the antagonist is not insulin, insulin-like growth factor, an anti-insulin receptor antibody, an anti-insulin-like growth factor receptor antibody, or fragments thereof.

2. The insulin-like growth factor receptor antagonist of claim 1, wherein the antagonist decreases insulin-like growth factor receptor activity in mammalian cells selected from the group consisting of breast cancer cells, pancreatic cancer cells, and myeloid cells.

3. The insulin-like growth factor receptor antagonist of claim 1, wherein the antagonist comprises SEQ ID NO:

1635.

4. A method of decreasing insulin-like growth factor receptor activity in insulin-like growth factor-responsive mammalian cells comprising:

contacting the cells with an insulin-like growth factor receptor antagonist in an amount sufficient to decrease the activity of the insulin-like growth factor receptor, wherein i) the antagonist comprises the Formula 2 sequence,

X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃, such that X₆ and X₇ are aromatic amino acids, X₈, X₉, X₁₁, and X₁₂ are any amino acid, and X₁₀ and X₁₃ are leucine;

ii) the antagonist further comprises two or more cysteines which are separated by at least 3 amino acids; and

iii) with the proviso that the antagonist is not insulin, insulin-like growth factor, an anti-insulin receptor antibody, an anti-insulin-like growth factor receptor antibody, or fragments thereof.

5. The method of claim 4, wherein the antagonist decreases insulin-like growth factor receptor activity in mammalian cells selected from the group consisting of breast cancer cells, pancreatic cancer cells, and myeloid cells.