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Cancer models and associated methods

A technology of cancer and models, applied in the field of prevention or treatment of diseases, disorders or diseases or their symptoms, capable of solving problems such as human debility

Pending Publication Date: 2016-08-03
NGM BIOPHARMLS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Unfortunately, this approach is often associated with serious, often debilitating adverse effects

Method used

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  • Cancer models and associated methods
  • Cancer models and associated methods
  • Cancer models and associated methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 4

[0144] Example 4 illustrates the effect on body weight of mice initially measured prior to injection of the indicated transgenes and subsequently determined at 3, 5 and 23 weeks post-injection. Such as Figure 4 Depicted in , transgenic db / db mice co-expressing the FGF19 variant M70 and FGF19 exhibited significant body weight loss compared to control-dosed animals, whereas that observed in mice expressing only the FGF19 transgene The effect on body weight was not significant. The body weight changes observed in mice co-expressing the FGF19 and M70 transgenes were also reflected in reduced liver weights compared to liver weights harvested from animals in the control group.

[0145] The effect of transgene expression on blood glucose was also assessed before transgene injection and at 3, 5, and 23 weeks post-injection in a manner similar to body weight measurements. Figure 5 The results presented in demonstrate that transgenic db / db mice co-expressing the FGF19 variant M70 an...

Embodiment 2

[0304] Materials and methods for Examples 2-5

[0305] The following methods and materials were used for Examples 2-5.

[0306] animal .Under controlled light (12 hours light and 12 hours dark cycle, 6:30p.m.-6:30a.m. dark), temperature (22±4℃) and humidity (50%±20%) , db / db mice (The Jackson Laboratory, Bar Harbor, ME) (approximately 15-week-old mice and approximately 36-48 g body weight at the start of treatment) were cared for according to welfare guidelines. Mice had free access to autoclaved distilled water and ad libitum access to a commercial diet (Harlan Laboratories, Indianapolis, IN, Teklad Global 18% Protein Rodent Diet) containing 1 kcal % fat, 24 kcal % protein and 58 kcal % carbohydrates. All animal studies were approved by the NGM Institutional Animal Care and Use Committee (NGM Institutional Animal Care and Use Committee).

[0307] Nucleic Acid and Amino Acid Sequences . FGF19 ORF (ORF encoding cDNA of hFGF19 (GenBank Accession No. NM_005117.2) and its en...

Embodiment 2

[0317] Plasma FGF19 levels in db / db mice after gene delivery

[0318] A 24-week study was performed to assess whether the FGF19 variant M70 could prevent FGF19-induced tumorigenesis in db / db mice. As an alternative to conventional delivery methods, AAV was used as a vehicle in this example (and subsequent examples 2-4) to deliver and express relevant exogenous genes in mice and achieve continuous, sustained, and systemic exposure to The proteins encoded by these transgenes.

[0319] Prior to gene delivery, mice were divided into six groups (5 male mice / group) as described in Table 1, and blood glucose and body weight measurements were recorded for each mouse.

[0320] Table 1

[0321]

[0322] At week 0, mice were injected with 0.2 mL of saline or 0.2 mL of one of the AAV constructs from groups 2-6. At weeks 3 and 5, blood glucose and body weight measurements were again recorded for each mouse in groups 1-6.

[0323] Five weeks after gene delivery, FGF19 concentrations ...

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Abstract

Models useful in determining whether fibroblast growth factor 19 variant polypeptides having glucose-lowering activity and / or anti-obesity activity also exhibit favorable oncology-related profiles, and methods and uses associated therewith are provided. Also provided are methods of antagonizing the oncogenic activity of FGF19 in a subject and, in certain embodiments, methods of preventing or treating a disease, disorder or condition, such as a FGF19-dependent disease, disorder or condition, or a symptom thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Serial No. 61 / 896,473, filed October 28, 2013; U.S. Serial No. 61 / 922,586, filed December 31, 2013; and U.S. Serial No. 62 / 067,273, filed October 22, 2014 , each of which is incorporated herein by reference in its entirety. technical field [0003] Among other things, the present invention relates to models that can be used to determine whether polypeptide variants of fibroblast growth factor having glucose-lowering activity also display favorable oncology-related features, and to the aforementioned methods and uses. Also provided are methods of antagonizing the oncogenic activity of FGF19 in a subject, and in certain embodiments, methods of preventing or treating a disease, disorder or condition (eg, an FGF19-dependent disease, disorder or condition) or a symptom thereof. Background of the invention [0004] Diabetes mellitus is a debilitating disease of the beta-cells of t...

Claims

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Application Information

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IPC IPC(8): A61P3/10
CPCG01N33/74G01N2800/04G01N2800/042G01N2800/7066A61K38/1825A61P1/04A61P1/16A61P11/00A61P13/08A61P3/04A61P35/00A61P3/10A01K67/0275C12Q1/6806A01K2227/105A01K2267/0331G01N33/5088G01N2800/7028
Inventor 雷·灵
Owner NGM BIOPHARMLS
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