Differential gene expression in physiological and pathological angiogenesis
Inventors
St. Croix, Brad • Seaman, Steven
Assignees
US Department of Health and Human Services
Publication Number
US-8440411-B2
Publication Date
2013-05-14
Expiration Date
2027-06-28
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Abstract
Methods of inhibiting pathological angiogenesis in a subject are disclosed. In particular examples, the method includes administering a therapeutically effective amount of a composition to a subject wherein the composition includes a specific binding agent that preferentially binds to one or more pathological angiogenesis marker proteins including Vscp, CD276, ETSvg4 (Pea3), CD137(4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, and collagen VIIIα1. In additional examples, methods to deliver a therapeutic agent to a brain or liver endothelial cell are also disclosed.
Core Innovation
The invention provides methods of inhibiting pathological angiogenesis in a subject by administering a therapeutically effective amount of a composition that includes a specific binding agent which preferentially binds one or more pathological angiogenesis marker proteins such as Vscp, CD276, ETSvg4 (Pea3), CD137 (4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, and collagen VIIIα1. The invention also discloses methods to deliver therapeutic agents to brain or liver endothelial cells using compositions including specific binding agents targeting brain- or liver-specific endothelial markers.
The problem being addressed is the need to selectively inhibit pathological angiogenesis, for example in tumor vessels, without affecting physiological angiogenesis such as during normal growth or wound healing. Current angiogenesis-based therapies lack the ability to differentiate between pathological and physiological angiogenesis, limiting selective targeting and increasing potential side effects. Additionally, there is a need for organ-specific endothelial markers to selectively deliver therapeutic and diagnostic agents to specific anatomical sites like the brain or liver.
The invention solves these problems by identifying multiple endothelial cell markers that are specific to pathological angiogenesis and organ-specific endothelial markers for brain and liver. By isolating endothelial cells from normal, regenerating, and tumor-bearing tissues and performing serial analysis of gene expression (SAGE), genes that are specifically overexpressed during pathological angiogenesis were identified. The invention also discloses compositions including specific binding agents (such as antibodies) that recognize these markers, which can be conjugated to therapeutic or diagnostic agents to inhibit pathological angiogenesis or enable selective delivery of agents to brain or liver endothelium.
Claims Coverage
The patent contains one independent claim focusing on a method for determining pathological angiogenesis using specific expression markers. The claim discloses inventive features regarding the detection and comparison of specific markers related to pathological angiogenesis.
Method of determining pathological angiogenesis by detecting specific markers
The method involves contacting a sample from a subject with probes or primers for CD276 and Ptprn (IA-2), detecting expression products of these markers, and determining the presence of pathological angiogenesis by comparing expression levels to a control where increased expression indicates pathological angiogenesis.
Detection includes additional markers
In addition to CD276 and Ptprn, the method can include detecting expression of CD137 (4-1BB), MiRP2, Apelin, ankylosis, or combinations thereof.
Indication of tumor presence through marker detection
Detection of increased expression of the at least two markers in a sample indicates the presence of a tumor in the subject.
Expression products can be RNA or protein
The detected expression products may be either RNA or protein forms of the markers.
Detection methods encompass multiple assay formats
The detecting step may be performed using serial analysis gene expression (SAGE), polymerase chain reaction (PCR), Western blot, immunoassay, microscopy, flow cytometry, spectrometry, or combinations thereof.
Sample sources for detection
The sample analyzed can be a serum sample obtained from the subject.
Defined primer sets for marker detection
The patent specifies primer sets for detecting CD276 and Ptprn (IA-2), for example, CD276 primers with sequences SEQ ID NOs: 211 and 212 and Ptprn primers with SEQ ID NOs: 227 and 228.
The independent claim covers a method that specifically detects pathological angiogenesis by identifying increased expression of endothelial markers CD276 and Ptprn (IA-2) in a subject's sample, optionally including other markers, using various detection methods, to indicate pathological angiogenesis or tumor presence. The claim specifies primer sequences to detect these markers.
Stated Advantages
Selective reduction or inhibition of pathological angiogenesis while minimizing effects on physiological angiogenesis.
Targeting endothelial cells, which have higher genomic stability and longer lifespans than tumor cells, reduces likelihood of therapy resistance.
Enables selective delivery of therapeutic or diagnostic agents to specific organs such as brain or liver, improving targeting and potentially reducing side effects.
Provides tumor-specific vascular targeting markers that can be conjugated to cytotoxins, chemotherapeutic agents, or imaging agents for improved cancer therapy and diagnosis.
Documented Applications
Inhibiting pathological angiogenesis associated with tumors to treat cancers including liver, breast, colon, and lung cancer.
Selective delivery of therapeutic agents to brain endothelial cells to evoke therapeutic responses or enable delivery across the blood-brain barrier.
Selective delivery of therapeutic agents to liver endothelial cells to evoke therapeutic responses or permit imaging.
Screening subjects for pathological angiogenesis or tumor presence by detecting expression of pathological angiogenesis marker proteins or nucleic acids in biological samples.
Conjugation of therapeutic molecules (e.g., cytotoxins, chemotherapy agents, radionucleotides) to antibodies specific for pathological or organ-specific endothelial markers for targeted treatment.
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