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IGF antagonist peptides

a technology of peptides and antagonists, applied in the field of peptides, can solve the problems of limited use of igf and igfbp in screening, preventing, or treating disease, and restricting the generation of specific igf-1 antagonists

Inactive Publication Date: 2006-07-06
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides peptides that can antagonize the biological activities of insulin growth factors (IGFs) and can be used to treat disorders involving IGF-1-mediated events. The peptides are specifically designed to bind to IGF-1 and prevent its interactions with other molecules. The peptides can be administered alone or in combination with other agents such as cytotoxic agents, polyethylene glycols, or other pharmaceutically acceptable carriers. The invention also provides methods for using the peptides to treat mammals with disorders involving IGF-1-mediated events. The peptides can be measured in body samples from mammals to determine their concentration and increase the risk for the disorder.

Problems solved by technology

Exploitation of the interaction between IGF and IGFBP in screening, preventing, or treating disease has been limited, however, because of a lack of specific antagonists.
IGF antagonists whose mechanism of action is via blockade of interactions at the IGF-1R interface may also significantly alter insulin action at the insulin receptor, a disadvantage of such antagonists.
Generation of specific IGF-1 antagonists has been restricted, at least in part, because of difficulties in studying the structure of IGF and IGFBP.

Method used

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  • IGF antagonist peptides

Examples

Experimental program
Comparison scheme
Effect test

example 1

Experimental Procedure

Construction of Polyvalent Naïve Peptide Libraries

[0208] Libraries were constructed using the method of Sidhu et al., Methods Enzymol., 328: 333-363 (2000) with a phagemid containing an IPTG-inducible Ptac promoter driving the expression of open reading frames encoding fusion proteins of the following form: the STII secretion signal (MKKNIAFLLASMFVFSIATNAYA; SEQ ID NO:8), followed by a random peptide (i.e., a member of the naïve peptide library), followed by a linker (GGGSGGG; SEQ ID NO:9), followed by the M13 gene-8 major coat protein

(AEGDDPAKAAFNSLQASATEYIGYAWAMVVVIVGATIGIKLFKKFTSKAS; SEQ ID NO:10).

Twenty-two different peptide libraries were constructed as shown in Table 1. Phage displaying the naïve libraries were purified by precipitation with PEG / NaCl as described in Sidhu et al., supra, and stored frozen at −70° C.

Isolation of IGF-1 Binding Peptides from Naïve Peptide-Phage Libraries

[0209] IGF-1 was obtained in house as described in U.S. Pat. No...

example 2

Structure Determination of IGF-F1-1 by NMR

[0233]1H NMR data were collected on peptide IGF-F1-1 either in pure H2O solution (30° C., pH 5.1 and 5.0 millimolar concentration) or in H2O containing 6% (v / v) d6-DMSO (40° C., pH 5.2 and at a concentration of 6.7 millimolar). In addition to one-dimensional spectra, two-dimensional double-quantum-filtered correlation spectroscopy (2QF-COSY), total correlation spectra (TOCSY), and rotating-frame Overhauser effect spectra (ROESY) were collected. The experiments were recorded as described by Cavanagh et al. in Protein NMR Spectroscopy Principles and Practice (Academic Press, San Diego; ISBN 0-12-164490-1, 1995), except that pulsed-field gradients were used for coherence selection in the 2QF-COSY (van Zijl et al., J. Magn. Reson., 113A: 265-270 (1995)) and excitation sculpting was used to suppress the water resonance in the TOCSY and ROESY experiments (Hwang and Shaka, J. Magn. Reson., 112A: 275-279 (1995)). After lyophilization and dissoluti...

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Abstract

Peptides are provided that antagonize the interaction of IGF-1 with its binding proteins, insulin receptor, and IGF receptor. These IGF antagonist peptides are useful in treating disorders involving IGF-1 as a causative agent, such as, for example, various cancers.

Description

RELATED APPLICATIONS [0001] This application is a divisional application of co-pending application Ser. No. 10 / 098,093 filed on Mar. 13, 2002, which is a non-provisional appication filed under 37 CFR 1.53(b)(1), claiming priority under 35 USC 119(e) to provisional application No. 60 / 275,904 filed Mar. 14, 2001, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention is directed to peptides that antagonize insulin-like growth factor (IGF), in particular, IGF-1. These peptides are useful in treating disorders caused or mediated by IGFs, such as cancer. [0004] 2. Description of Related Disclosures [0005] There is a large body of literature on the actions and activities of IGFs (IGF-1, IGF-2, and IGF variants). Human IGF-1 is a 7649-dalton polypeptide with a pI of 8.4 (Rinderknecht and Humbel, Proc. Natl. Acad. Sci. USA, 73: 2365 (1976); Rinderknecht and Humbel, J. Biol. Chem., 253: 2769 (1978)) belong...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K7/08A61K38/00A61K39/395G01N33/53A61K45/00A61P3/10A61P5/24A61P9/10A61P17/00A61P17/02A61P35/00A61P43/00C07K7/06C07K14/47G01N33/574
CPCA61K38/00C07K14/4743C07K2299/00A61P13/12A61P17/00A61P17/02A61P27/02A61P35/00A61P43/00A61P5/24A61P9/10A61P3/10
Inventor DESHAYES, KURT D.LOWMAN, HENRY B.SCHAFFER, MICHELLE L.SIDHU, SACHDEV S.
Owner GENENTECH INC
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