Image analysis – Applications – Biomedical applications
Reexamination Certificate
2000-04-26
2004-02-03
Boudreau, Leo (Department: 2621)
Image analysis
Applications
Biomedical applications
C359S201100
Reexamination Certificate
active
06687395
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the analysis of biological markers using Microvolume Laser Scanning Cytometry (MLSC). The invention includes instrumentation for performing MLSC, a system for analysis of image data obtained from the instrumentation, and an informatics system for the coordinated analysis of biological marker data and medical information.
BACKGROUND OF THE INVENTION
As a result of recent innovations in drug discovery, including genomics, combinatorial chemistry and high throughput screening, the number of drug candidates available for clinical testing exceeds the pharmaceutical industry's development and economic capacity. In 1998, the world's top pharmaceutical and biotechnology companies spent more than $50 billion on research and development, more than one-third of which was spent directly on clinical development. As the result of a number of factors, including increased competition and pressure from managed care organizations and other payors, the pharmaceutical industry is seeking to increase the quality, including the safety and efficacy of new drugs brought to market, and to improve the efficiency of clinical development.
Recent drug discovery innovations, therefore, have contributed to a clinical trials bottleneck. The numbers of therapeutic targets being identified and lead compounds being generated far exceed the capacity of pharmaceutical companies to conduct clinical trials as they are currently performed. Further, as the industry currently estimates that the average cost of developing a new drug is approximately $500 million, it is prohibitively expensive to develop all of the potential drug candidates
The pharmaceutical industry is being forced to seek equivalent technological improvements in drug development. Clinical trials remain very expensive and very risky, and often decision making is based on highly subjective analyses. As a result, it is often difficult to determine the patient population for whom a drug is most effective, the appropriate dose for a given drug and the potential for side effects associated with its use. Not only does this lead to more failures in clinical development, it can also lead to approved products that may be inappropriately dosed, prescribed, or cause dangerous side effects. With an increasing number of drugs in their pipelines, pharmaceutical companies require technologies to identify objective measurements of a drug candidate's safety and efficacy profile earlier in the drug development process.
Biological markers are characteristics that when measured or evaluated have a discrete relationship or correlation as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. Pharmacologic responses to therapeutic intervention include, but are not limited to, response to the intervention generally (e.g., efficacy), dose response to the intervention, side effect profiles of the intervention, and pharmacokinetic properties such as the rate of drug metabolism and the identity of the drug metabolites. Response may be correlated with either efficacious or adverse (e.g., toxic) changes. Biological markers include patterns of cells or molecules that change in association with a pathological process and have diagnostic and/or prognostic value. Biological markers may include levels of cell populations and their associated molecules, levels of soluble factors, levels of other molecules, gene expression levels, genetic mutations, and clinical parameters that can be correlated with the presence and/or progression of disease. In contrast to such clinical endpoints as disease progression or recurrence or quality of life measures (which typically take a long time to assess), biological markers may provide a more rapid and quantitative measurement of a drug's clinical profile. Single biological markers currently used in both clinical practice and drug development include cholesterol, prostate specific antigen (“PSA”), CD4 T cells and viral RNA. Unlike the well known correlations between high cholesterol and heart disease, PSA and prostate cancer, and decreased CD4 positive T cells and viral RNA in AIDS, the biological markers correlated with most other diseases have yet to be identified. As a result, although both government agencies and pharmaceutical companies are increasingly seeking development of biological markers for use in clinical trials, the use of biological markers in drug development has been limited to date.
There is a need for a biological marker identification system that is capable of sorting through the vast amounts of information needed to establish the correlation of the biological markers with disease, disease progression and response to therapy. Such a biological marker identification system is described in U.S. Provisional Patent Application Serial No. 60/131,105, entitled “Biological Marker Identification System”, filed Apr. 26, 1999, and in the commonly-owned United States Utility Application filed concurrently with this application, entitled “Phenotype and Biological Marker Identification System,” both of which are specifically incorporated herein by reference in its entirety. This technology includes the instrumentation and assays required to measure hundreds to thousands of biological markers, an informatics system to allow this data to be easily accessed, software to correlate the patterns of markers with clinical data and the ability to utilize the resulting information in the drug development process. The system extensively utilizes Microvolume Laser Scanning Cytometry (MLSC).
In preferred embodiments of the marker identification system, a biological fluid is contacted with one or more fluorescently-labeled detection molecules that can bind to specific molecules in that fluid. Typically, the biological fluid is a blood sample, and the detection molecule is a fluorescent dye-labeled antibody specific for a cell-associated molecule that is present on, or within, one or more sub-types of blood cell. The labeled sample is then placed in a capillary tube, and the tube is mounted on a MLSC instrument. This instrument scans laser light through a microscope objective onto the blood sample. Fluorescent light emitted from the sample is collected by the microscope objective and passed to a series of photomultipliers where images of the sample in each fluorescent channel are formed. The system then processes the raw image from each channel to identify cells, and then determines absolute cell counts and relative antigen density levels for each type of cell labeled with a fluorescent antibody.
Marker MLSC can also be used to quantitate soluble factors in biological fluids by using a microsphere-bound primary antibody to the factor along with a secondary fluorescently-labeled antibody to the factor. The factor thereby becomes bound to the microsphere, and the binding of the secondary antibody fluorescently labels the bound factor. The system in this embodiment measures the fluorescent signal associated with each bead in the blood sample in order to determine the concentration of each soluble factor. It is possible to perform multiple assays in the same sample volume by using multiple bead types (each conjugated to a different primary antibody). In order to identify each bead type, the different beads can have distinct sizes or can have a different internal color, or each secondary antibody can be labeled with a different fluorophore.
Although preferred embodiments of the invention use antibodies to detect biological markers, any other detection molecule capable of binding specifically to a particular biological marker is contemplated. For example, various types of receptor molecules can be detected through their interaction with a fluorescently-labeled cognate ligand.
The raw data from the MLSC instrument is processed by image analysis software to produce data about the cell populations and soluble factors that were the subject of the assay. This data is then transferred to a database. Other data that can be stored
Chung Chih-Hua
Dietz Louis J.
Kantor Aaron B.
Lee Byron
Norton Scott
Boudreau Leo
Miller Ryan J.
SurroMed, Inc.
Swanson & Bratschun LLC
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