A p60 Polypeptide Variant Stimulates NK Cells and Reduces Tumor Size In Vivo

NJH ID: #10-08

Background
Natural killer cells (or NK cells) are cytotoxic lymphocytes that, when appropriately activated, play a major role in the rejection of tumors and cells infected by viruses. NK cells kill infected or cancerous target cells by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis (programmed cell death). They also secrete cytokines that can regulate innate and adaptive immune responses. Thus, strategies to therapeutically activate NK cells have potential use in treatment of infections and tumors and improving adaptive immune responses to these agents and vaccines. Since activated NK cells also contribute to successful pregnancy, such strategies might also be used to promote successful full-term pregnancy.

There are currently few therapeutically viable strategies to activate NK cells in patients. Use of non-specific immune stimulants such as Toll-like receptor (TLR) agonists are minimally effective and elicit toxicity. Antibodies to certain NK cell surface markers are in some cases effective, but target specific NK cell subsets and may not work in all patients due to allelic differences in NK cell surface proteins recognized by the antibodies. Antibodies may also cause depletion of NK cells or only activate specific functions of NK cells. We have developed an approach for activating a large proportion of mouse and human NK cells under conditions conducive to effective therapy.
 
Technology
All species of the genus Listeria secrete a major extracellular protein called p60. The laboratory of Dr. Lenz at National Jewish Health has shown that the wildtype p60 protein promotes NK cell activation and created a mutant form of p60 that retains this ability to activate NK cell but lacks enzymatic endopeptidase activity that could result in unwanted side effects when the protein is administered to patients. They found that both forms of p60 contribute to the activation of naïve mouse and human NK cells due to the ability of p60 to appropriately stimulate another immune cell type, dendritic cells (DC).
 
Potential Applications
Treatment of diseases that will benefit from NK cells activation:
•  Cancer. Evidence points to a positive association between NK cell activation and positive outcomes in solid, metastatic and hematologic cancers.
•  Infectious diseases. NK cells are implicated in resistance to numerous viral infections prevalent in the US and other countries; including upper respiratory infections, HSV, EBV, VZV, HPV, CMV.
•  Vaccines. P60 appears to act directly on naïve DCs to stimulate their maturation in a manner that permits activation of NK cells. Both activated DCs and IFN that is produced by NK cells can boost cellular (Th1-type) immune responses. P60 may be useful to improve immune responses elicited by vaccines and thus be useful for vaccinating large numbers of people world wide.
•  Pregnancy. NK cells are found in the placenta and their activation has been associated with positive pregnancy outcome. There may be utility in stimulating NK cell function with p60 to prevent pre-eclampsia and improve pregnancy success in individuals suffering recurrent miscarriages.
 
State of Development
Investigators at NJH have identified a region of the p60 protein that is necessary and sufficient to elicit NK cell activation. Small polypeptides that contain this region retain functionality and when administered to mice reduce tumor size in a cancer model. Modified versions of these polypeptides may show increase stability (and thus activity).
 
Publications
Schmidt, Rebecca L., Holly C. Filak, Jack D. Lemon, Terry A. Potter, and Laurel L. Lenz. "A LysM and SH3-Domain Containing Region of the Listeria Monocytogenes P60 Protein Stimulates Accessory Cells to Promote Activation of Host NK Cells." Ed. Mary X. D. O'riordan. PLoS Pathogens 7.11 (2011): E1002368.  PMID: 22072975.
Schmidt, Rebecca L., and Laurel L. Lenz. "Distinct Licensing of IL-18 and IL-1β Secretion in Response to NLRP3 Inflammasome Activation." Ed. David M. Ojcius. PLoS ONE7.9 (2012): E45186.  PMID: 23028835.

Patent Status
Published international patent WO 2011/060093.

Inventors
Laurel L. Lenz, Ph.D., Rebecca Schmidt, Ph.D.

Licensing Status
This technology is available for licensing.

For Further Information, Contact:
Emmanuel Hilaire, PhD
Manager
Technology Transfer Office
National Jewish Health
1400 Jackson Street, Room M206b
Denver, CO 80206
Voice: 303.398.1262
Fax: 303.270.2352
HilaireE@njhealth.org

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