Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1999-12-27
2002-04-02
Chin, Christopher L. (Department: 1641)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S009100, C435S004000, C435S007100, C435S007210, C435S007220, C435S007310, C435S007320, C435S029000, C436S501000, C436S815000
Reexamination Certificate
active
06365129
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is toxicology testing, particularly toxicology testing in pharmaceutical research and development.
2. Background of the Invention
During the drug development process, potential therapeutic agents or drug candidates must be demonstrated to be both safe and effective for their intended use prior to obtaining FDA approval and subsequent commercialization, at least in the United States. In drug development processes, potential drug candidates are subjected to mutagenicity and toxicology assessments in an effort to demonstrate safety. Mutagenicity analyses take place in bacteria (Ames test), Drosophila (Mueller-5 test), and in mammalian cell culture. However, toxicology analyses are limited to mammalian cell culture and animal model studies. This scheme requires significant time and money to be invested to analyze the toxicity of a candidate drug. As such, toxicology studies are typically performed after successful efficacy assessment for drug candidates.
With the advent of high throughput drug discovery, there is great interest in the pharmaceutical and related industries to streamline the toxicology testing segment of the drug development process. As the number of drug candidates has exploded from 10's per year to 1,000's per year, the toxicology assessment programs have become a severe bottleneck in the drug development process.
Accordingly, there is great interest in the development of new high throughput screening assays which are capable of rapidly providing toxicity data for a large number of different compounds. Of particular interest would be the development of an in vivo high throughput toxicity screening assay.
RELEVANT LITERATURE
High throughput toxicity screening assays are discussed in: Kelly, “Advances in HTS Toxicology,” Genetic Engineering News, Mar. 1, 1999, pg. 14; and Sansome, Drug Discovery Today (1999) 4: 199-201.
SUMMARY OF THE INVENTION
High throughput toxicology screening assays are provided. In the subject methods a plurality of different compound compositions, usually at least 10 different compound compositions, are simultaneously assayed for their toxic activity, if any. Each compound composition in the plurality is assayed for toxicity by contacting it with a population of multi-cellular organisms and determining the effect of the compound composition on the multi-cellular organisms. Multi-cellular organisms that find use in the subject high throughput screening (HTS) assays are those that are small, have differentiated tissues and organs, have a rapid generation time, and are prolific. The subject HTS methods find use in a variety of applications, and are particularly suited for use in the toxicological screening of large numbers of compounds, such as combinatorially produced libraries of compounds.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
A high throughput toxicology screening method is provided. In the subject method, at least 10 different compound compositions are tested simultaneously. Each compound composition is tested by contacting it with a plurality, e.g. from about 10 to 1000, non-mammalian multi-cellular organisms and determining the effect of the compound composition on the organisms. The multi-cellular organisms employed in the subject methods are small, have differentiated tissues and organs, have a rapid generation time, and are prolific. The subject high throughput screening methods find use in a variety of applications, and are particularly suited for use in the toxicology screening of libraries of compounds, such as libraries of combinatorially produced compounds.
Before the subject invention is described further, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present invention will be established by the appended claims.
In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.
As summarized above, the subject invention provides a high throughput screening (HTS) method for simultaneously testing the toxicology of a plurality of different compound compositions. The subject HTS assays are in vivo toxicology assays, by which is meant that they determine the effect of a compound on a living, multi-cellular organism. As such, the subject HTS assays are distinguished from in vitro assays, in which cell cultures are employed.
In the subject HTS assays, a plurality of different compounds are simultaneously tested. More specifically, a plurality of different compound compositions are simultaneously tested. Different compound compositions differ from each other in at least one of the following characteristics: (a) they are made up of compounds that differ by molecular formula; or (b) they are made up of compounds of the same molecular formula but the compounds are present in different concentrations. In other words, any two given compound compositions are different if they are either made up of compounds that differ by molecular formula or are made up of the same type of compound but differ with respect to concentration of that compound. For example, a plurality of different compound compositions may include 4 different types of compounds that differ by molecular formula, where each specific type of compound is present in three different concentrations, such that the plurality is made up of 12 different compound compositions.
By simultaneously tested is meant that each of the compound compositions in the plurality are tested at substantially the same time. Thus, all of the compound compositions in the plurality are assayed for their toxicological effects in parallel. The number of compound compositions in the plurality of compound compositions that are simultaneously tested is typically at least about 10, where in certain embodiments the number may be at least about 100 or at least about 1000, where the number of compound compositions tested may be higher. In general, the number of compound compositions that are tested simultaneously in the subject HTS methods ranges from about 10 to 10,000, usually from about 100 to 10,000 and in many embodiments from about 1000 to 5000.
In the subject methods, each individual compound composition in the plurality is individually assayed for toxicology. Each compound composition is individually assayed for its toxicity by contacting the compound composition with a plurality of non-mammalian multi-cellular organisms and determining the effect of the compound composition (or lack thereof) on the organisms of the plurality. As the organisms employed in the subject methods are multi-cellular, they include differentiated tissues and organs. They are further characterized by being relatively small, where by small is meant at least about 0.001 g, usually at least about 0.01 g and more usually at least about 0.1 g, where the average mass of each organism in the plurality may be as great as 10 g or greater, but typically does not exceed about 100 g and usually does not exceed about 1,000 g. The multi-cellular organisms employed in the subject HTS methods are also characterized by having a rapid generation time. A rapid generation time is important to maintain the breeding colony plus supply enough organisms that will be prolific enough to produce on average at least about 100 progeny per day, which is the minimum requirement for high throughput screening. For Drosophila, this minimum population of flies can range from 10 to 300, usually from 50 to 150.
A number of different types of non-mammalian multi-ce
Bozicevic, Field & Francis
Chin Christopher L.
Field Bret E.
Tosk, Inc.
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