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Predicting tumor response to anti-ERBB3 antibodies

A technology for antibodies and tumors, applied in anti-tumor drugs, antibody medical components, measuring devices, etc., can solve problems such as non-benefit

Active Publication Date: 2014-07-30
AVEO PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, patients with breast cancer whose ERBB2 (HER2) gene is amplified may benefit from the use of trastuzumab treatment with trastuzumab, however patients without ERBB2 gene amplification may not benefit from treatment with trastuzumab

Method used

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  • Predicting tumor response to anti-ERBB3 antibodies
  • Predicting tumor response to anti-ERBB3 antibodies
  • Predicting tumor response to anti-ERBB3 antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Example 1: Xenograft Tumor Response to AV-203

[0116] Tumor response to AV-203 was assessed as follows. To establish xenograft tumors, use medium including 10% fetal bovine serum and keep tumor cells in a culture medium including 5% CO 2 Initial growth was performed in culture at 37 °C in an atmosphere. Subsequently, the cells were inoculated into the flanks of 8-week-old female NCR nude mice or CB.17SCID mice (Taconic Labs) at a volume of 2-10x10 6 cells / mouse in 50% matrigel (BD Biosciences, Cat. No. 356237). Tumors were measured twice weekly using vernier calipers. The volume of the tumor was calculated using the following formula: Width x Width x Length / 2. When the tumor reaches about 200mm 3 At , mice were randomly divided into two groups, 10 mice per group, and were administered intraperitoneally (IP) with PBS vehicle control or AV-203 at 20 mg / kg twice a week. In some studies, a second control group was used that received human IgG twice weekly at 20 mg / ...

Embodiment 2

[0121] Example 2: Relationship between AV-203 response and NRG1 levels

[0122] For the 25 tumors evaluated, RNA was prepared from untreated healthy tumors. Using Covaris CryoPrep TM system (Covaris Inc.Model CP-02) pulverized the fast-frozen tumor samples. Transfer approximately 30 mg of comminuted tumor material to 2 mL of SafeLock TM tube (Eppendorf, No. 02236652). 1 mL of TRIzol (Invitrogen, Cat. No. 15596-026) and one (5 mm) stainless steel mixer bead (Qiagen, Cat. No. 69989) were added to each tube. Then, place the tube in the Tissue Lyser II TM (Qiagen, Cat. No. 85300) for cell lysis. The samples were shaken for 2 cycles of 30 seconds each. The stand is then rotated and shaken again for 2 more cycles.

[0123] Total RNA (aqueous phase) was extracted from cell lysates by adding 200 [mu]L chloroform to each sample. The samples were shaken vigorously for 15 s and centrifuged at 12000 rpm for 15 min at 4 °C. Transfer the supernatant (350 μL) to a new 2 mL SafeLoc...

Embodiment 3

[0128] Example 3: Relationship between AV-203 response and ERBB3 levels

[0129] ERBB3 levels were also determined from these 25 tumor models by quantitative RT-PCR as described for NRG1. AV-203 tumor growth inhibition in these 25 tumors was then plotted against the expression level of ERBB3 in each tumor (expressed as Ct value). Such as Figure 13 As shown, even though ERBB3 is a target of AV-203, tumor growth inhibition was not correlated with increased ERBB3 expression.

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Abstract

A diagnostic method for predicting quantitatively whether a human tumor will be sensitive or resistant to treatment with an ERBB3 inhibitor, e.g, an anti-ERBB3 antibody, is disclosed. The method is based on measurement of NRG1 expression at the RNA level, or at the protein level, in a tissue sample from the tumor.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit and priority of U.S. Provisional Application Serial No. 61 / 636,183, filed April 20, 2012, and U.S. Provisional Application Serial No. 61 / 544,206, filed October 6, 2011, each of which is filed in its entirety at Incorporated herein by reference. technical field [0003] The fields of the invention are molecular biology, oncology and clinical diagnostics. Background technique [0004] Most cancer drugs are effective in some patients but not in others. This result arises from genetic variation between tumors and can even be observed in multiple tumors from the same patient. In the case of targeted therapy, altered patient responses were specifically announced. Thus, the full potential of targeted therapies cannot be realized without appropriate tests in place to determine which patient will benefit from which drug. According to the National Institutes of Health (NIH), the term "biom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/574
CPCG01N33/574A61P35/00G01N2333/4756G01N2800/52A61K39/39558C12Q1/6881
Inventor S·文森特K·密特泽冯斌S·泰勒S·伯特加R·尼克洛缇D·迈克因特施J·盖乌里斯
Owner AVEO PHARM INC
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