Immunoglobulin E antibodies
In order for someone to become allergic, their mast cells capture and display antibodies, specifically immunoglobulin E (IgE) antibodies, for that specific allergen. This enables the mast cells to recognize – and react to – the same allergen upon re-exposure.
“If you have a peanut allergy and have had a response to peanuts in the past, then your immune cells made IgE antibodies against peanut proteins, and the mast cells collected them,” Scott said. “Now, they are waiting for you to eat another peanut. When you do, they can respond within minutes, and if the response is strong enough, it can result in anaphylaxis.”
To selectively target mast cells to respond to a particular allergen, the researchers designed their therapy to engage only mast cells carrying IgE antibodies for that allergen. The nanoparticle uses a protein allergen to engage with IgE antibodies on the mast cells and then uses an antibody to engage the Siglec-6 receptor to shut down the mast cell’s ability to react. And because only mast cells display Siglec-6 receptors, the nanoparticle cannot bind to other cell types – a strategy that effectively limits side effects.
“You can use any allergen that you want, and you will selectively shut down the response to that allergen,” Scott said. “The allergen would normally activate the mast cell. But at the same time the allergen binds, the antibody on the nanoparticle also engages the inhibitory Siglec-6 receptor. Given these two contradictory signals, the mast cell decides that it shouldn’t activate and should leave that allergen alone. It selectively stops a response to a specific allergen. The beauty of this approach is that it does not require killing or eliminating all the mast cells. And, from a safety standpoint, if the nanoparticle accidentally attaches to the wrong cell type, that cell just won’t respond.”
Preventing anaphylaxis in humanized mouse model
After demonstrating success in cellular cultures using human tissue-derived mast cells, the researchers moved their therapy into a humanized mouse model. Because mast cells in mice do not have the Siglec-6 receptor, Bochner’s team developed a mouse model with human mast cells in their tissues. The researchers exposed the mice to an allergen and delivered the nanotherapy at the same time.
No mice experienced anaphylactic shock and all survived.
“The simplest way to monitor an allergic response is to track changes in body temperature,” Scott said. “We saw no changes in temperature. There was no response. Also, the mice remained healthy and did not display any outward signs of an allergic reaction.”
Bochner explained: “Mouse mast cells do not have Siglec-6 on their surface like in humans, but we got as close as we could for now to actual human studies by testing these nanoparticles in special mice that had human mast cells in their tissues. We were able to show that these humanized mice were protected from anaphylaxis.”
Next, the researchers plan to explore their nanotherapy for treating other mast cell-related diseases, including mastocytosis, a rare form of mast cell cancer. They also are investigating approaches to loading drugs inside the nanoparticles to selectively kill mast cells in mastocytosis without injuring other cell types.