A p60 Polypeptide Variant Stimulates NK Cells and Reduces Tumor Size In Vivo
NJH ID: #10-08
Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitutes a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. They kill cells by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis (programmed cell death). Stimulation of NK cells can be used to treat infections and tumors, to improve adaptive immune responses to these agents and vaccines, and possibly to promote successful full-term pregnancy.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system.Current technologies that use TLR agonists have been showed to elicit toxicity. Others lack the ability to stimulate NK cell responses. Antibodies to NK cell surface markers in some cases activate only 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. Therefore a more effective approach to activate the innate immune system through NK cells is currently lacking.
All species of the genus Listeria secrete a major extracellular protein called p60. The laboratory of Dr. Lenz at National Jewish Health has purified the wildtype p60 protein and created a mutant form of p60 that lacks endopeptidase activity. They found that both forms of p60 contribute to the activation of dendritic cells (DC) in a manner that permits the activation of naïve NK cells. The enzymatically-null mutant p60 protein lacks the potential “off-target” effects, thus is an improvement over the wildtype p60 protein.
Treatment of diseases that will benefit from NK cells activation:
Cancer. Evidence point 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 IFNy 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 have been shown to reduce tumor size in a cancermouse model. Modified versions of these polypeptides may show increase stability (and thus activity).
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.
Published international patent WO 2011/060093.
Laurel L. Lenz, Ph.D., Rebecca Schmidt, Ph.D.
This technology is available for licensing.
For Further Information, Contact:
Emmanuel Hilaire, PhD
Technology Transfer Office
National Jewish Health
1400 Jackson Street, Room M206b
Denver, CO 80206