Anti-IGF-1R antibodies and uses thereof

A technology of IGF-1R and IGF-1, applied in the direction of antibodies, antibody mimics/stents, anti-tumor drugs, etc., can solve the problem of not effectively blocking biological functions

Inactive Publication Date: 2010-09-22
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, an anti-IGF-1R antibody approach that effectively blocks biological functions mediated by both IGF-1 and IGF-2 may provide enhanced efficacy over other approaches that do not effectively block the tumor microenvironment Biological functions of IGF-1R signaling mediated by both IGF-1 and IGF-2 in

Method used

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  • Anti-IGF-1R antibodies and uses thereof
  • Anti-IGF-1R antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0676] Select IGF-1R specific Fab from phage library

[0677] Use recombinant human IGF-1R extracellular domain to screen for 3.5×10 10 A unique cloned human primitive phagemid Fab library (Hoet, R.M., et al. Nat Biotechnol. 23(3): 344-8 (2005), ("Hoet et al.") which is incorporated herein by reference in its entirety). Two different panning arms were performed using biotinylated IGF1R-his and IGF1R-Fc proteins. Prior to incubation with the phage library, the protein was captured on magnetic beads coated with streptomycin antibiotic protein. In the case of IGF1R-Fc, the biotinylated anti-Fc antibody is captured on magnetic beads, followed by capturing the Fc fusion protein. Choose as described in Hoet et al. After 3 rounds of panning, the 479bp gene III residue was removed by MluI digestion, and the vector was reconnected to express soluble Fab in TG1 cells. The ELISA analysis of 920 clones from the biotinylated IGF1R-his arm yielded 593 positive clones, which contained 33 spe...

Embodiment 2

[0679] Binding activity of Fab to IGF-1R expressed on tumor cells

[0680] The ability of Fab to bind to wild-type IGF-1R was determined by flow cytometry using the MCF-7 tumor cell line.

[0681] MCF-7 cells (human breast adenocarcinoma from NCI) were divided 24 hours before setting up the assay to obtain a 70% confluent monolayer. Generally, the MCF-7 cell line is maintained within 20 passages. Cells are floated with cell dissociation buffer (Gibco catalog No. 13151-014), counted, washed and adjusted to 1×10 6 Cells / ml, then add 1 ml of cells to each tube (12 x 75 mm tube, Falcon catalog No. 352054). The cells were compressed into a pellet and centrifuged at 1200 rpm for 5 min to remove the supernatant, and then 100 μl of the diluted antibody was added to the cell pellet. The purified Fab was tested at a starting concentration of 210 or 60 μg / ml and diluted 1:3 to 0.001 μg / ml in FACS buffer. The FACS buffer used in the whole assay process contains 1% BSA (Sigma catalog number ...

Embodiment 3

[0686] Fab inhibits the binding of ligand and IGF-1R

[0687] Radioimmunoassay (RIA) was used to determine the ability of Fab to block the binding of IGF-1 and IGF-2 ligands to IGF-1R.

[0688] Ligand Blocking Assay (RIA). Recombinant human IGF-1 (catalog number 291-G1), IGF-2 (catalog number 292-G2), insulin (catalog number Custom02) human insulin receptor (catalog number 1544-1R) were purchased from R&D Systems, Inc., Minneapolis, MN. Insulin (Arg-Insulin, catalog number 01-207) was purchased from Upstate Cell Signaling Solutions (Lake Placid, NY (now part of Millipore, Concord, MA (USA)). 125 I-rhIGF-1 (catalog number IM172), 125 I-rhIGF-2 (catalog number IM238) and 125 I-rhInsulin (catalog number IM 166) was purchased from Amersham Biosciences (Piscataway, NJ). AffiPure goat anti-human IgG, an Fcγ fragment specific antibody (catalog number 109-005-098, Jackson ImmunoResearch, West Grove, PA) was used for IGF-1R-Fc capture. As the detection antibody, goat anti-mouse IgG HRP (...

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Abstract

The invention relates to antibodies which bind to insulin like growth factor receptor -1 (IGF-IR) and uses thereof, in particular in the diagnosis and treatment of cancer. Specific human and murine monoclonal antibodies which inhibit IGF-lR-mediated pro-survival and tumor proliferation pathways, and variants, fragments, and derivatives thereof are provided. Also provided are specific human and murine monoclonal antibodies capable of synergistically inhibiting the ability of the ligands, insulin like growth factor 1 (IGF-I) and insulin like growth factor 2 (IGF-2), to bind to IGF-IR; as well as fragments, variants and derivatives of such antibodies. Antibodies of the invention produce such synergistic effects via allosteric and / or competitive inhibition of IGF-IR ligand binding.

Description

[0001] Cross references to related applications [0002] This application requires the rights of U.S. Provisional Application No. 60 / 968,540 filed on August 28, 2007 in accordance with Section 119(e) of the Patent Law of Title 35 of the United States Code. This application also relates to U.S. Patent Application No. 11 / 727,887 filed on March 28, 2007, pursuant to Section 119(e) of the Patent Act of Title 35 of the U.S. Code, which requires section 60 / filed on March 28, 2006 Benefits of U.S. Provisional Application No. 786,347 and U.S. Provisional Application No. 60 / 876,554 filed on December 22, 2006. Each of the above cited patent applications is hereby incorporated by reference in its entirety. Background technique [0003] Several epidemiological studies have shown that higher than normal circulating levels of IGF-1 are associated with an increased risk of several common cancers, including breast cancer (Hankinson et al., Lancet 1998.351:1393-6), prostate cancer (Chan Et al., ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/30C12P21/08
CPCC07K16/2863C07K2316/52C07K2317/34C07K2319/00C07K2317/21C07K2317/77A61K2039/507A61K2039/505C07K2317/55C07K2317/56C07K2316/96C07K2317/52C07K2317/73C07K2317/76A61P35/00A61P35/02A61P43/00
Inventor 斯蒂芬·德马雷斯特坎德萨米·哈里哈兰
Owner BIOGEN MA INC
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