Mast cells (MCs) are a type of white blood cell active in the immune system. They are produced in the bone marrow and play a key role in the inflammatory process. Additionally, they are the primary driver of allergic reactions, facilitating the degranulation of histamines when bound by an allergen.
Mastocytosis is a rare ,but serious condition in which neoplastic mast cells grow uncontrollably. Cutaneous mastocytosis, also referred to as urticaria pigmentosa, is typically found in children and generally causes mild to moderate symptoms. This form of mastocytosis is low-risk, and generally resolves on its own.
Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are serious conditions that currently cannot be cured. They are characterized by aggressive, uncontrolled growth of mast cells. Given the nature of these cells there is a high risk of metastasis, making prognosis very poor. MCL is among the most aggressive forms of cancer and is generally unresponsive to traditional treatments. ASM is treated symptomatically but results are mixed at best.
We discovered that Siglec-7, a transmembrane protein originally identified on Natural Killer cells, is also expressed on the surface of human mast cells and responsible for releasing inhibitory signals to the cell. We also found that using an anti-Siglec-7 antibody we could activate Siglec-7, therefore inhibiting mast cell activation. This pathway has the potential to inhibit the growth and proliferation of mast cells found in mastocytosis by causing cell inhibition and death.
Co-cross-linking of Siglec-7 with an activation receptor ensures that regular non-cancerous mast cells will not be killed in this process. These healthy cells will simply be inhibited so they do not release histamines (one of the causes of mastocytosis symptoms). Through this process we have shown that cancerous mast cells can be removed while their non-cancerous counterparts remain viable.
This Mechanism can be directed also to the treatment of respiratory disease, e.g: severe Asthma disease.
Triggering of Siglec-7 by our anti-Siglec-7 antibody leads to tumor/mastocytosis death.
Tumor cells/ mastocytoma express a variety of receptors, both activating (shown in shades of blue) and inhibitory (shown in shades of red). Several current therapies use blocking antibodies (upper, black) to prevent the activating receptors from being ligated, depriving the cells of activating signals and leading to tumor death (upper row). We propose to use agonist anti-Siglec-7 antibodies (bottom green) to cause signaling by the inhibitory receptor Siglec-7, causing extensive inhibition and therefore mastocytosis cell death (lower row). Yellow glow indicates a signaling receptor.
Seeking funding for ongoing research and industrial collaboration to advance to clinical trials
This therapy may be suitable for other indications as well in the respiratory area as well as Eosinophilia
There are no other effective treatments or cures currently on the market, so a therapeutic based on this technology has the potential to take the entire market.
Francesca Levi-Schaffer, Full Professor, HU