Monoclonal antibody and antigens for diagnosing and treating lung disease and injury
Inventors
Clauss, Matthias • Petrache, Irina • Voswinckel, Robert
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-10450371-B2
Publication Date
2019-10-22
Expiration Date
2032-06-08
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Abstract
The present invention provides methods for diagnosing a patient with emphysema, COPD of lung injury caused by tobacco use by detecting the levels of EMAP II in a sample. Disclosed herein are the hypervariable regions for a rat monoclonal antibody that binds to a form of EMAP II. This disclosure also includes a polypeptide sequence included in EMAP II that is the target for the binding of the antibody to its target protein. This epitope serves as the basis for a humanized antibody that can be used to treat patients that suffer from pathologies that exhibit elevated levels of EMAP II expression.
Core Innovation
The present invention provides methods for diagnosing and treating patients with emphysema, chronic obstructive pulmonary disease (COPD), or lung injury caused by tobacco use by detecting the levels of endothelial monocyte activating protein II (EMAP II) in biological samples. The invention includes hypervariable regions of a rat monoclonal antibody that binds to a form of EMAP II, polypeptide sequences included in EMAP II serving as antibody binding targets, and humanized antibodies derived from these epitopes to treat patients with pathologies exhibiting elevated EMAP II expression.
The problem addressed is that COPD, including emphysema, is a prevalent and fatal disease characterized by irreversible destruction and enlargement of lung airspaces impairing gas exchange. Despite its high mortality and prevalence, there is no effective treatment to reverse or halt COPD progression. Mechanisms underlying emphysema, including inflammation, protease imbalance, and excessive apoptosis of alveolar cells, are not fully understood, and current models fail to account for permanent lung destruction seen uniquely in emphysema. Thus, there is a need for early diagnostic methods and effective treatments targeting mechanisms involved in emphysema progression.
The invention provides a diagnosis method by detecting overexpression of EMAP II in patient samples such as serum, plasma, lung lavage, or tissue biopsy, using immunological or nucleic acid-based methods compared to controls. It also discloses treatment methods by administering therapeutically effective amounts of EMAP II neutralizing compounds including antibodies, CXCR3 receptor agonists, siRNA, or antisense RNA, administered systemically or by inhalation. Additionally, the invention offers antibodies and epitopes specific for EMAP II forms, methods to produce such antibodies, and kits for diagnosis and monitoring treatment efficacy.
Claims Coverage
The patent includes one independent claim focused on a method of making an antibody that binds to EMAP II using a specific epitope polypeptide. The inventive features center on the immunization step, B-cell selection process, and identification of antibodies binding EMAP II.
Method of making an antibody using a specific EMAP II epitope polypeptide
A method comprising contacting the immune system of a mammal with a polypeptide consisting of SEQ ID NO: 12 to induce antibody production, followed by selecting a B-cell from the mammal that produces antibodies binding to endothelial monocyte activating protein II (EMAP II).
Immunization of mammal with EMAP II epitope
Contacting the immune system of the mammal includes immunizing the mammal with the specified polypeptide to elicit an immune response producing antibodies targeting EMAP II.
Selection of B-cell producing EMAP II antibodies
Selecting a B-cell from the mammal involves isolating B-cells, fusing them with myeloma cells to form hybridomas, and choosing at least one hybridoma that produces antibodies binding EMAP II as identified by ELISA screening.
The claims primarily cover a method of producing antibodies that specifically bind to EMAP II by immunizing a mammal with a defined epitope polypeptide and selecting antibody-producing hybridomas, including the steps of immunization and hybridoma screening for EMAP II binding.
Stated Advantages
Early detection of emphysema or COPD by measuring EMAP II levels enables diagnosis in early stages, potentially leading to more effective treatments and better patient prognosis.
Neutralizing EMAP II activity with antibodies or other compounds can inhibit lung endothelial cell apoptosis and inflammation, thus potentially halting or reducing emphysema progression.
Administration of EMAP II neutralizing agents via inhalation targets local lung tissue effectively, reducing required doses and minimizing systemic side effects.
Use of humanized antibodies targeting specific EMAP II epitopes allows for safe and effective therapeutic intervention in humans and other mammals.
The transgenic animal models and detection kits provided facilitate the evaluation and monitoring of therapeutic efficacy in emphysema and COPD treatment.
Documented Applications
Diagnosis of patients with emphysema or COPD by detecting overexpression of EMAP II in biological samples such as serum, plasma, bronchoalveolar lavage fluid, or lung biopsy.
Predicting susceptibility of smokers or ex-smokers to develop emphysema or COPD by measuring EMAP II expression levels.
Treatment of emphysema and COPD patients by administering therapeutically effective amounts of EMAP II neutralizing compounds including monoclonal or humanized antibodies, CXCR3 receptor agonists, siRNA, or antisense RNA targeting EMAP II or CXCR3.
Monitoring treatment effectiveness in emphysema and COPD by measuring changes in EMAP II expression levels during therapy.
Use of transgenic mouse models overexpressing EMAP II to study disease mechanisms and evaluate therapeutic agents.
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