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Antibodies for use in the prophylactic and/or treatment of bacterial infections, cancer metastasis and Alzheimer's disease.

Country of Origin: Spain
Reference Number: TOES20191104001
Publication Date: 4 November 2019

Summary

A Spanish research institution has discovered that the absence of one specific protease (MT4-MMP - Membrane type 4-matrix metalloproteinase) in patrolling monocytes increases their surface level of the alphaMbeta2 integrin receptor, which in turn increases its patrol function. This increased activity may offer a new therapeutic strategy for acute pathological processes. They are looking for partners, with no preferred location, to establish a license agreement.

Description

A Spanish research institution has been studying that patrolling monocytes, a type of white blood cell, exhibits unique functions in the vasculature in homeostasis and in inflammatory disease. Classical monocytes can migrate into damaged and infected tissues where they differentiate into inflammatory macrophages, whereas patrolling monocytes have been reported in several disease settings to survey the endothelium and remove damaged cells and debris from the vasculature, having been associated with wound healing and the resolution of inflammation in injured tissues. Patrolling monocytes (PMo) exert their surveillance activity within the vasculature, where they recognize endothelial damage and promote repair. Crawling of PMo on the inflamed endothelium has been reported to be dependent on αMβ2 integrin.

The matrix metalloproteinases (MMPs) are enzymes involved in the processes of tumor growth, invasion (direct extension and penetration by cancer cells into neighboring tissues) and metastasis. They are frequently overexpressed in malignant tumors. Membrane-type 4 matrix metalloproteinase (MT4-MMP) is anchored to the plasma membrane and it has been suggested to promote breast cancer metastasis and glial cancers (a general term for numerous tumors of the central nervous system). MT4-MMP can cleave αM integrin (Itgam) and its absence leads to enhanced αM integrin-dependent crawling of patrolling monocytes. The researchers have shown for the first time that the absence or deficiency of MT4-MMP proteolytic activity enhances the levels of αM integrin receptor, which in turn increases the activity of patrolling monocytes. Also for the first time, the inventors disclose MT4-MMP-mediated cleavage of αM integrin (Itgam) as a mechanism for regulating PMo crawling and extravasation to the target tissue.

The researchers have demonstrated in a MMP knock out mouse model that the absence of this specific MMP increases bacterial clearance and improves survival against a systemic infection by Listeria monocytogenes. In addition, in vivo data showed that the absence of MMP in monocytes results in a significant reduction of the number of lung melanoma metastasis. This is why researchers propose that MT4-MMP inhibition might offer a new therapeutic strategy for the treatment of those diseases wherein an improvement of the activity of patrolling monocytes would be beneficial, such as bacterial infections, cancer metastasis and Alzheimer disease. Non-specific inhibitors such as TIMP1 (metallopeptidase inhibitor 1) can reduce the activity of MT4-MMP. However, researchers propose its specific inhibition by antibodies directed against its catalytic domain. They have studied some anti-MT4-MMP antibodies that showed to be specific, to bind to the native protein and to have MT4-MMP inhibitory activity. Finally, they selected the monoclonal antibody LEM-3/10, which recognized the native human and mouse MT4-MMP.

The research center is looking to establish a license agreement with a biotech or pharmaceutical company working in alternative prophylactic methods or/and treatments for bacterial and virus infections, tumor metastasis or neurodegenerative diseases, preferably in Alzheimer’s disease.

Advantages and Innovations

•	Non-specific inhibitors can reduce the activity of MT4-MMP, but researchers propose its selective inhibition by antibodies directed against its catalytic domain. 
• The monoclonal antibody LEM-3/10 has very specific reactivity against the native protein and has MMP inhibitory activity.
• MT4-MMP inhibition may offer a new therapeutic strategy for acute pathological processes, wherein an improvement of the activity of patrolling monocytes would be beneficial. This improvement will promote:
- A better fight against circulating metastatic cells, particularly to the lung.
- A better fight against bacterial and virus infectious agents.
- A decrease of deposits in cerebral amyloid angiopathy in Alzheimer's disease.

Stage Of Development

Field tested/evaluated

Stage Of Development Comment

Tested in animal models.

Requested partner

The research center is seeking for biotech or pharmaceutical companies working in alternative prophylactic methods or/and treatments for bacterial and virus infections, tumor metastasis or neurodegenerative diseases, preferably in Alzheimer’s disease. The partner would complete all the steps needed to commercialize the technology.

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