Immunotherapy has proven to be effective against many serious diseases. But to treat diseases in the brain, the antibodies must first get past the obstacle of the blood-brain barrier. In a new study, a research group at Uppsala University describes their development of a new antibody design that increases brain uptake of antibodies almost 100-fold.
Immunotherapy entails treatment with antibodies; it is the fastest growing field in pharmaceutical development. In recent years, immunotherapy has successfully been used to treat cancer and rheumatoid arthritis, and the results of clinical studies look very promising for several other diseases. Antibodies are unique in that they can be modified to strongly bind to almost any disease-causing protein. In other words, major potential exists for new antibody-based medicines.
The problem with immunotherapy for diseases affecting the brain is that the brain is protected by a very tight layer of cells, called the blood-brain barrier. The blood-brain barrier effectively prevents large molecules, such as antibodies, from passing from the bloodstream into the brain. It has therefore been difficult to use immunotherapy to treat Alzheimer’s and Parkinson’s disease, which affect the brain, as well as cancerous tumours in the brain.
It has been known for a long time that some large proteins are actively transported across the blood-brain barrier. These include a protein called transferrin, whose primary task is to bind to iron in the blood and then transport it to the brain. The research group behind this new study has taken advantage of this process and modified the antibodies they want to transport into the brain using components that bind to the transferrin receptor. Then, like a Trojan horse, the receptor transports antibodies into the brain. The number of modifications to and placement of the antibodies have proven to be important factors for making this process as effective as possible.
“We’ve placed them so that each antibody only binds with one modification at a time, despite being modified in two places. Our design thus doubles the chances of the antibody binding to the transferrin receptor compared with only one modification. We’ve successfully increased the amount of antibodies in the brain almost 100-fold, which is the largest uptake improvement that has ever been shown,” says Greta Hultqvist, researcher at the Department of Public Health and Caring Sciences at Uppsala University.
To try out the new format, researchers have used it on an antibody that binds to a protein involved in the course of Alzheimer’s disease. Without the modification, they could only detect very small quantities of antibody in the brain in a mouse model of Alzheimer’s disease, while they could detect high levels of the modified antibody in the same mice.
“From a long-term perspective, it’s likely that the new format can be used to effectively treat not only Alzheimer’s disease, but also other diseases affecting the brain,” says Dag Sehlin, researcher at the Department of Public Health and Caring Sciences at Uppsala University.
University of Saskatchewan (U of S) scientists have developed a new immunotherapy technique that nearly eliminates the allergic response to peanut and egg white proteins in food-allergic mice, reducing the anaphylactic response by up to 90 per cent with only one treatment.
“This discovery reverses food allergies in mice, and we have many people with allergies volunteering their own cells for us to use in lab testing to move this research forward,” said professor John Gordon, lead scientist behind the discovery just published in the current issue of the Journal of Allergy and Clinical Immunology.
The findings open the door to test this new allergy treatment in “humanized mice”—mice with non-existent immune systems implanted with cells from a human immune system, for example, from a peanut-allergic person. With Health Canada approval, the first human trial could begin in about one year, Gordon said.
“If we can reliably ‘cure’ food allergies, or related conditions such as asthma or autoimmune diseases such as multiple sclerosis with this new therapy, it would be life-changing for affected individuals.”
Roughly 2.5 million Canadians self-report having at least one food allergy. Anaphylaxis, defined as a severe rapid-onset allergic reaction, can be life-threatening and treatment options are limited.
The discovery involves generating a type of naturally occurring immune cell that sends a signal to reverse the hyper-immune response present in allergic reactions. That signal triggers another “off switch” that turns off reactive cells further along the allergic pathway.
“We predict the treatment could be on the market within the next five to 10 years,” said Gordon, who is also a research leader in the Allergy, Genes and Environment (AllerGen) Network. AllerGen—part of the federally funded Networks of Centres of Excellence program—aims to help Canadians address the challenges of living with asthma, allergies, anaphylaxis and related immune diseases.
Gordon’s team will collaborate with other AllerGen investigators located at the U of S, McGill University, Queen’s University, McMaster University, and University of Alberta to pilot the new technique.
“This discovery portends a major breakthrough towards a therapeutic reversal of food allergen sensitivity,” said Dr. Judah Denburg, scientific director and CEO of AllerGen. “The treatment prevents anaphylactic responses in what were previously fully sensitive mice, opening the door for translating this therapy into the clinic.”
There is compelling evidence this technique could be effective in humans. In 2010, Gordon’s team demonstrated they could reverse an asthmatic response in human cells in a test tube. Using three applications of a similar therapy in a 2012 study, the researchers effectively eliminated asthma in afflicted mice, within only eight weeks.
“Even if we only cure 25 per cent of subjects, we will dramatically improve the health of those individuals, and also reduce healthcare system expenses,” said Gordon, who worked with Wojciech Dawicki, a research associate and the primary author and lead researcher in this study. Master’s student Chunyan Li and lab technicians Xiaobei Zhang and Jennifer Town also worked on the project.
Here’s how the technique works:
- The key component of this research is dendritic cells, which serve as the gate-keepers of the immune system and are present in tissues in contact with the external environment, such as the skin and the inner lining of the nose, lungs, stomach and intestines.
- Gordon’s pioneering treatment involves producing dendritic cells in a test tube and then exposing them to a unique mix of proteins, a vitamin A-related acid naturally occurring in the human gut, and to the allergen, in this case, peanut or ovalbumin (egg white protein). The modified dendritic cells are then reintroduced into the mouse.
- Using this technique, the researchers were able to nearly eliminate the allergic reaction by converting allergen-sensitive immune cells into cells that mimic the response seen in healthy, non-allergic individuals.
The treatment reduced the observed symptoms of anaphylaxis, and lowered other key protein markers in the allergic response by up to 90 per cent.
Food allergy is a growing public health issue in Canada. Currently, there is no known cure. According to the Canadian Institute for Health Information, an estimated 171,000 Canadians visited emergency rooms for allergic reactions from 2013 to 2014, the rate of anaphylaxis visits increased by 95 per cent from 2006 to 2014, and the severity of reactions is increasing.
Gordon said the new technique also shows promise for treating autoimmune disorders such as multiple sclerosis. “It would take very little to adapt the therapy for autoimmune diseases,” he said.
Radiation therapy not only kills cancer cells, but also helps to activate the immune system against their future proliferation. However, this immune response is often not strong enough to be able to cure tumours, and even when it is, its effect is limited to the area that has been irradiated. Now, however, research to be presented to the ESTRO 35 conference has shown that the addition of an immune system-strengthening compound can extend the radiation therapy-induced immune response against the tumour sites and that this response even has an effect on tumours outside the radiation field.
Ms Nicolle Rekers, MSc, from the Department of Radiation Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands, will describe to the conference how a combination of radiation therapy and L19-IL2, an immunotherapy agent, can increase significantly the immune response when given to mice with primary colorectal tumours. L19-IL2 is a combination of an antibody that targets the tumour blood vessels and a cytokine, a small protein important in cell signalling in the immune system.
The researchers found not only that the mice were tumour-free following treatment, but also that when re-injected with cancer cells 150 days after cure, they did not form new tumours. There was also an increase in the number of cells with an immunological memory.
Macrophages are cells of the immune system that protect the host from invading pathogens. But in cancer, macrophages can be “hijacked” by tumors, and made to support their malignant growth and spread. This is a drawback for a major cancer treatment, immunotherapy, which turns the body’s immune system against the tumor. EPFL scientists, working with colleagues at the Roche Innovation Centers in Munich and Basel, have now identified a molecular “switch” that can convert the “hijacked” macrophages into cells that can stimulate the immune system to fight the growth and spread of cancer. The work is published in Nature Cell Biology.
Along with attacking foreign pathogens like bacteria, macrophages also help the body’s organs develop and its wounds heal. Their own behavior is fine-tuned by small molecules that they produce, called microRNAs.
When a tumor begins to develop, macrophages attempt to block its growth. But often tumors hijack them and convert them into what are known as “tumor-associated macrophages”, or TAMs for short.
Now corrupted, TAMs use their microRNAs to shield the tumor from the patient’s immune system, helping it grow and metastasize. This phenomenon is common across many tumor types. It is one of the major obstacles in treating cancer, and often leads to a poor prognosis for the patient.
Michele De Palma’s team at EPFL found how to reclaim TAMs. The researchers genetically modified TAMs to remove their ability to produce microRNAs. As a result, the TAMs were reprogrammed dramatically. Instead of protecting the tumor, the TAMs now signaled the presence of the tumor to the immune system, triggering attacks against it – and did so very efficiently.