Emapii neutralizing antibody limits influenza A virus (IAV)-induced lung injury
Inventors
Bogatcheva, Natalia • Clauss, Matthias Alexander • March, Keith L.
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-10899829-B2
Publication Date
2021-01-26
Expiration Date
2037-02-23
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
EMAPII is a monocyte- and endothelial cell-activating protein with prominent pro-apoptotic activity on endothelial and epithelial cells. Provided herein are compositions and methods for treating or preventing endothelial and epithelial apoptosis induced by EMAPII. More particularly, provided herein are compositions and methods for treating or preventing Influenza A virus (IAV)-induced weight loss, impairment of blood oxygenation, lung edema, and endothelial/epithelial apoptosis associated with IAV infections. In addition, anti-EMAPII therapy provides a novel complementary treatment strategy to existing anti-viral and anti-inflammatory approaches.
Core Innovation
The invention provides compositions and methods for treating or preventing endothelial and epithelial apoptosis induced by EMAPII, a monocyte- and endothelial cell-activating protein with prominent pro-apoptotic activity. More particularly, the invention addresses methods for treating or preventing influenza A virus (IAV)-induced weight loss, impairment of blood oxygenation, lung edema, and endothelial/epithelial apoptosis associated with IAV infections by administering EMAPII-neutralizing antibodies or binding portions thereof.
The problem being solved is the lack of therapies for endothelial and epithelial lung damage caused by viral infections such as influenza A, despite existing antiviral treatments and vaccines. Lung edema, caused by endothelial and epithelial barrier dysfunction and cell death, reduces the lung's ability to oxygenate blood and contributes to morbidity and mortality. Current treatments focus on antiviral and anti-inflammatory approaches but do not address endothelial and epithelial apoptosis leading to lung injury. There is an unmet medical need for therapies that protect the lung by limiting virus-induced injury independent of viral resistance issues.
Claims Coverage
The patent includes claims directed to methods involving EMAPII-neutralizing antibodies for treating influenza-induced lung injury, reducing apoptosis, and modulating inflammatory responses. Two main independent claim groups are identified, covering treatment of lung injury and inflammation with antibodies containing specific heavy and light chain hypervariable regions.
Use of EMAPII-neutralizing antibodies for treatment of virus-induced acute lung injury
A method of treating acute lung injury induced by influenza A virus infection by administering a therapeutically effective amount of an EMAPII-neutralizing antibody or binding portion thereof that includes specified heavy chain hypervariable regions (CDR1 of SEQ ID NO:5, CDR2 of SEQ ID NO:6, and CDR3 of SEQ ID NO:7) and light chain hypervariable regions (CDR1 of SEQ ID NO:8, CDR2 of SEQ ID NO:9, and CDR3 of SEQ ID NO:10), thereby treating conditions such as pneumonia, impairment of blood oxygenation, and lung edema.
Reduction of endothelial or epithelial cell apoptosis associated with influenza-induced lung injury
A method of reducing endothelial or epithelial cell apoptosis in the lung of a subject with lower respiratory viral infection by administering a therapeutically effective amount of an EMAPII-neutralizing antibody, fragment, or binding portion thereof containing the specified heavy and light chain hypervariable regions defined above.
Modulation of inflammatory macrophage phenotypes to reduce lung inflammation
A method of reducing lung inflammation in a subject with influenza-induced acute lung injury by administering a therapeutically effective amount of the specified EMAPII-neutralizing antibody or fragments thereof, resulting in an increase in anti-inflammatory macrophage phenotype (M2-like) and a decrease in the pro-inflammatory macrophage phenotype, with increases in markers such as IL10, CD206, and YM1, and reduction of TNF-α expression.
Together, these inventive features describe methods for treating influenza A virus-induced lung injury and associated damage by targeting EMAPII with neutralizing antibodies featuring specific complementarity-determining regions, providing therapeutic benefits through reducing apoptosis and modulating inflammatory responses.
Stated Advantages
EMAPII-neutralizing antibodies limit influenza A virus-induced weight loss, impairment of blood oxygenation, and lung edema in a murine model.
The therapy reduces endothelial and epithelial apoptosis, contributing to lung protection and recovery.
EMAPII mAb treatment shifts the inflammatory response from pro-inflammatory M1 macrophages to anti-inflammatory M2-like macrophages and increases regulatory T cells, promoting resolution of inflammation.
The approach offers a complementary treatment strategy to existing antiviral and anti-inflammatory therapies, potentially avoiding issues with antiviral resistance.
Documented Applications
Treatment or prevention of endothelial or epithelial lung damage associated with lower respiratory tract influenza A virus infection.
Reduction of endothelial or epithelial cell apoptosis in lungs during influenza A viral infection.
Reduction of lung inflammation in subjects with influenza-induced acute lung injury by modulating macrophage phenotypes and increasing regulatory T cells.
Interested in licensing this patent?