Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir

An IGF-IR, protein technology, applied in the field of new proteins, can solve the problems of difficult and ineffective treatment

Inactive Publication Date: 2010-01-27
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, none of these agents are suitable for long-term administration to human patients
Additionally, although IGF-I has been administered to patients to tr

Method used

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  • Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir
  • Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir
  • Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including igf-ir

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Experimental program
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Embodiment approach

[0237] In some embodiments, it may be preferable to glycosylate the proteins of the invention. Preferably, such proteins are fibronectin based scaffolds. Fibronectin-based scaffolds generally do not contain glycosylation sites, however, such glycosylation sites can be engineered into proteins.

[0238] Glycosylation of proteins is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are the recognition sequences for enzymatic attachment of the carbohydrate module to the asparagine side chain . These can be engineered into proteins of the invention, particularly fibronectin-based scaffold proteins and their corresponding polynucleotides. Thus, the presence of either of these two tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycos...

Embodiment 1

[0305] Example 1: Initial characterization of IEG-binding molecules

[0306] Based on the scaffold of human fibronectin X-type 3 domains, approximately 10 13 A library of RNA-protein fusion variants (amino acid numbering refers to SEQ ID NO: 1) (tricyclic library; Xu et al., Chemistry & Biology 9:933-942, 2002). After conversion to mRNA / cDNA heteroduplexes, a library of one trillion mRNA / cDNA-protein fusions is bound to 100 nM biotinylated IGF-IR in solution and captured to a streptavidin-coated magnetic beads on. The cDNA is eluted, amplified by PCR, and used to generate a new library of mRNA / cDNA-protein fusions. Five rounds of selection were performed in this manner, and after each round the percentage of bound IGF-IR in the library was monitored by quantitative PCR to identify enrichment for target binding ( figure 1 ).

Embodiment 2

[0307] Example 2: Identification of Competing IGF-IR Clones

[0308] Proteins encoded by independent clones were analyzed for inhibition of target binding using a competitive binding assay in the presence of IGF-IR. Over one hundred clones were identified as inhibiting IGF-I binding to IGF-IR, suggesting that these clones bind IGF-IR at or near the natural ligand (IGF-I) binding site. The SEQ ID NOs of these one hundred clones (see Figure 30 ) and their percent inhibition in competitive binding assays are presented in Table 1.

[0309]

[0310]

[0311]

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Abstract

The present invention provides innovative proteins that bind to insulin-like growth factor-I receptor (IGF-IR), as well as other important proteins. The invention also provides innovative proteins in pharmaceutical preparations and derivatives of such proteins and the uses of same in diagnostic, research and therapeutic applications. The invention further provides cells comprising such proteins, polynucleotide encoding such proteins or fragments thereof, and vectors comprising the polynucleotides encoding the innovative proteins.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Patent Application No. 60 / 860,605, filed November 22, 2006, and U.S. Provisional Patent Application No. 60 / 879,666, filed January 9, 2007, which are hereby incorporated by reference in their entirety these applications. field of invention [0003] The present invention relates to novel proteins that bind insulin-like growth factor-I receptor (IGF-IR), as well as other important proteins. The invention also relates to novel proteins and derivatives of such proteins in pharmaceutical formulations, and their use in diagnostic, research and therapeutic applications. The invention further relates to cells comprising such proteins, polynucleotides encoding such proteins or fragments thereof, and vectors comprising polynucleotides encoding the novel proteins. Background of the invention [0004] Insulin-like growth factor-I receptor (IGF-IR) is a transmembrane heterotetrameric protein, whi...

Claims

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Application Information

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IPC IPC(8): C07K14/47C07K14/78C12N15/10C12N9/12C40B40/02
Inventor 雷·坎普豪森戴维·法布里齐奥马丁·C·赖特帕特里克·盖奇约翰·门德莱因
Owner BRISTOL MYERS SQUIBB CO
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