The Race to Deliver the Hypoallergenic Cat

Home , Fel d 1, Hypoallergenic

Allergies outlook NILS JACOBI/GETTY Scientists are working on a feline vaccine that could block the protein most commonly associated with allergic reactions to cats. The race to deliver the hypoallergenic cat

Researchers are looking beyond allergen immunotherapy to help people whose pets make them sneeze. By Amber Dance

octor, if you tell me to get rid Hospital in Madrid. Up to 30% of people show Some researchers are trying to improve of the cat, I’m getting rid of sensitivity to cats in some regions. this immunotherapy, and others are trying my kids first,” said the parent The effects can be limited to sniffles and a different angle by injecting Fel d 1 antibod- of one young patient with sneezes for some people. For others, how- ies into people with allergies. Scientists are an allergy to the family pet. ever, the allergy can prompt dangerous also seeking ways to neutralize Fel d 1 before “DSandra Gawchik, an allergist in Chester, Penn- asthma attacks. A US study estimated that, it leaves the animal — or even stop cats from sylvania, knew they were only half-joking — among cat-sensitive people, 47% of emergency producing it entirely. she had heard similar threats before. Another hospital visits could be attributed to feline patient recounted being pushed out of the exposure1. And allergy is among the main rea- Sticky stuff house by his wife and daughter over his cat sons why owners send cats to shelters. Cats secrete the Fel d 1 protein from their allergy, saying they preferred the feline to him. Small doses of cat allergens — the major one salivary and sebaceous glands, and spread it Sensitivity to pets (cat and dog allergies being a small, sticky protein called Fel d 1 — throughout their fur during regular tongue occur at similar rates) is typically the second can help to build up tolerance over time. But baths. Released in shed skin and hair, it floats in most prevalent allergy in any region, after pol- treatments can cost US$800–1,000 annually, the air for hours, attaching to carpets, curtains len or mites, says Joaquin Sastre, an allergist require up to 100 injections over 3–5 years, and and clothing. Some cat owners with allergy at the Jiménez Díaz Foundation University are not always permanent or wholly effective. concerns invest substantial time in cleansing

Allergies outlook not only their houses but also their pets; weekly immunotherapy and a monthly infusion response, they will not build up tolerance. But however, the protein is difficult to eradicate. of antibodies against TSLP. Regeneron aims to circumvent this issue by dos- “You’d have to bathe the cat every other day,” “We hope to induce a state of tolerance that ing people directly with Fel d 1 IgG antibodies. says Gawchik. And because Fel d 1 sticks to would potentially occur more quickly, last The treatment is based on two IgG antibodies cat owners’ clothing, it can show up in places longer and reach a higher level,” says principal that cover up key IgE binding sites on either end where no feline has ever set paw. investigator Jonathan Corren, an allergist and of the allergen. Together, they can block up to Fel d 1’s tiny dimensions also make it a tricky immunologist at the University of California, 83% of the IgE–Fel d 1 interactions responsible customer. At less than one-tenth the size of Los Angeles. The group plans to publish its for most allergic reactions to cats. In a phase Ib a single ribosome, it can slip deep into the findings soon. “The results, at this point, do test, people with a cat allergy received a single lungs and trigger asthma, alongside itchy look promising,” Corren says. dose of the antibody combination4. Then, in eyes and nasal congestion. Despite these dif- The antibody therapy would be costly, four tests conducted between eight days and ficulties, however, cat allergy could be seen Corren adds, so would be best suited for nearly three months later, researchers sprayed as a low-hanging fruit for allergy researchers. people with severe allergies or asthma. But it cat hair extract into the participants’ nostrils. Although at least eight different cat proteins needn’t be restricted to those sensitive to cats. Symptoms dropped in 60% of participants, by can cause allergy, Fel d 1 is by far the major con- “The approach should be applicable to any an average of 60%, Orengo says. Regeneron is tributor. Tamping down a person’s response to number of allergens,” he says. now running a phase II trial. just this one protein, or reducing the presence Adiga Life Sciences in Huntingdon, UK, is The advantage of the antibodies, says of Fel d 1 in the cat and its environment, could trying a different approach, substituting Fel d 1 Orengo, is that they will work more quickly minimize symptoms across a wide swathe of for Cat-PAD, which consists of smaller, syn- than immunotherapies that require the patient feline-sensitive people. Unlike in dogs, which thetic peptides based on Fel d 1. The hope is to build tolerance. However, because the produce several key allergens, scientists need that a synthetic allergen would be less likely to patient will not be producing the antibodies only hit the bullseye once in cats. cause a reaction and could therefore be given themselves, regular boosters will be required, People who are allergic to Fel d 1 react by in higher doses — potentially enabling people perhaps quarterly. The team is also working on creating immunoglobulin E (IgE) antibodies. to achieve tolerance in just four treatments. a similar treatment against birch pollen, and These induce mast cells to spew out histamine In a phase II trial, 11 participants who received is considering other allergens, too. and other chemicals that create sneezing, itch- Cat-PAD saw their symptoms reduced for up to “This is certainly an interesting approach,” ing and congestion. A less unpleasant response 2 years2. But a 2016 phase III study failed when says Martin Bachmann, an immunologist at the to the protein would be one involving IgG anti- people receiving a placebo developed just as University of Bern. “But it’s probably going to bodies — the type made in response to viruses much tolerance to Fel d 1 as did those on the be kind of expensive.” — which are not generally associated with aller- immunotherapy. Mark Larché, an immunol- gic reactions. People who had cats as children ogist at McMaster University in Hamilton, Immune to the allergen and who have an overall lower risk of allergy Canada, and a consultant for the company, Bachmann is among the scientists who are tend to develop this kind of response, notes speculates that part of the problem might have targeting Fel d 1 in cats themselves. If the ani- Martin Chapman, chief executive of Indoor been that all the phase III participants had to mals did not produce the protein, this should Biotechnologies in Charlottesville, Virginia, be cat owners. As a result, even those in the prevent allergic reactions in most people. which specializes in products and laboratory placebo group would have daily exposure to But researchers are unsure how thoroughly services linked to indoor air quality, allergies Fel d 1, potentially promoting tolerance. the protein needs to be eliminated to have the and asthma. desired effect, as well as what happens to a cat Current immunotherapy for allergies trains “We hope to induce a state without Fel d 1. the body to make IgG antibodies that grab anti- No one knows what Fel d 1 does for felines. gens before IgE can lock on. The injections of tolerance that would Some cats have a little and some have a lot, so contain purified cat allergens, or a broader potentially last longer and large amounts don’t seem to be necessary. And mix of cat proteins. Overall, immunotherapy reach a higher level.” the cat’s breed doesn’t seem to make much is up to 70% effective, says Gawchik, but it only difference; even hairless Sphynx cats make works “if the patient religiously gets shots, on Fel d 1. On average, unneutered males have a weekly basis”, and some people return for Adiga is now planning a trial with non-cat- the most and females the least, suggesting booster injections years later because their owners. Larché says that participants will be the protein might carry hormones or phero allergies have returned. Sastre says that nearly tested for allergy symptoms by sending them mones. But it has also been hypothesized to one-third of his patients still need some form to cat cafes (theme cafes where patrons can protect cats’ skin. of anti-allergy medication, such as antihista- watch or play with cats). The company is also In 2013, Bachmann co-founded HypoPet, mines, to keep their symptoms in check. And in pursuing peptide-based immunotherapy for a spin-off company from the University of some cases, the small doses of allergen cause allergies to grass3 and dust mites, Larché says, Zurich in Switzerland. The firm aims to cre- the very reactions they are meant to stifle. That and has designed peptides for birch allergy — a ate hypoallergenic cats by vaccinating them is why researchers see room for improvement. common problem in northern Europe and the against their own Fel d 1, so that the cat’s IgG The Immune Tolerance Network, a collab- northeastern United States. antibodies block the protein before it is sniffed oration funded by the US National Institute All of these immunotherapies ultimately rely up by a human. of Allergy and Infectious Diseases, hopes to on patients generating “a very specific immune Bachmann built the vaccine out of recom- make immunotherapy work better and faster response to the allergen”, says immunologist binant Fel d 1, a bit of tetanus toxin peptide by interfering with an allergy-driving protein Jamie Orengo at Regeneron Pharmaceuticals, and the coat from a plant virus. “The immune called thymic stromal lymphopoietin (TSLP). a biotechnology company in Tarrytown, New system thinks it’s a virus,” he says, and accord- In a phase I and II trial, participants received York. If a person cannot make a potent enough ingly responds with IgG (see ‘Immunizing cats

Chapman hopes that his team at Indoor HypoPet, a spin-o company from the University of Zurich in Switzerland, aims to create hypoallergenic Biotechnologies will be able to make a truly cats by vaccinating them against their own Fel d 1 protein, so that the cat’s immunoglobulin G (IgG) hypoallergenic feline by eliminating Fel d 1 antibodies block the protein before it is snied up by a human. completely. They are in the early stages of developing a gene therapy against the two Activated B cells secrete anti-Fel d 1 antibodies genes that encode the subunits of Fel d 1. Elim- Vaccination inating them from the salivary and sebaceous activates the cat's immune glands should create a hypoallergenic cat. system Chapman and his colleagues first had the idea in the 1990s, when the Fel d 1 genetic sequences were identified10, but the rise of CRISPR gene-editing technology has provided an opening to try it. Chapman already holds a Anti-Fel d 1 IgG antibodies circulate patent on the idea, but it will take a lot of work through the cat's Plasma cell secreting before allergen-free kitties are on offer. body and bind to Fel d 1-specific antibodies Nicole Brackett, a postdoctoral researcher the allergen Fel d 1 at the company, has analysed the Fel d 1 The vaccine is built out of recombinant Fel d 1, sequences of dozens of cats. From this, she was Fel d 1 allergen a bit of tetanus toxin peptide and the coat from a plant virus. able to design guide RNAs that can be used to

Antibody against Fel d 1 bring about a CRISPR-based disruption of the

ADAPTED FROM REF. 5 REF. FROM ADAPTED Fel d 1 genes. So far, she has managed to destroy the Fel d 1 sequences in an immortalized cat against their own allergen’). In an early test, company Nestlé Purina in St Louis, Missouri, kidney cell line, with efficiencies of up to 55%. the level of Fel d 1 in the tears of 18 cats fell offers an antibody-coated product that is The company plans to treat cats individu- by more than half 42 days after vaccination5. designed to neutralize the feline allergen. ally, rather than breed hypoallergenic kittens, “Every cat makes a good IgG response,” he says, Known as Pro Plan LiveClear, it was released so it needs a way to deliver the gene therapy to and the vaccine doesn’t seem to cause them earlier this year in the United States, Europe the glands in grown cats. Brackett is consider- any problems. and Russia, and is expected to launch in other ing using a viral vector in an injected or topical The team then tested the vaccine in 13 cats territories in 2021. solution. “We will definitely be watching this owned by 10 people with cat allergies. They Ebenezer Satyaraj, an immunologist at space,” says Orengo. But she notes that even if asked the owners to report on their symp- Nestlé Purina, was inspired by personal expe- Chapman and Brackett could eliminate Fel d 1 toms, as well as how long they could stand to rience — his daughter broke out in a rash after from a customer’s cat, the owner would still be pet their cat before it became uncomfortable. visiting a cat-owning friend. When he and his likely to encounter the ubiquitous allergen. Seven of the pet owners saw their symptoms colleagues started looking for a way to neutral- Ideally, Bachmann says, allergy sufferers decrease, and 8 of them were able to extend ize Fel d 1, they landed on chicken antibodies. would take a multi-pronged approach. “You their petting time from an average of 16.9 min- The chicken version of IgG is called IgY, want to tackle it from both ends,” he says. utes before the vaccine to 27.7 minutes after6. says Satyaraj, and this can be found in the egg “You desensitize the allergic humans; at the Bachmann isn’t sure how long the vaccine’s powder that has long been used to supplement same time you render the cat hypoallergenic.” effect will last, and annual booster injections animal foodstuffs. His team contracted with a Gawchik is intrigued that LiveClear cat food might be necessary. Another challenge Hypo- company that exposed hens to Fel d 1, so that might allow her patients to take exactly that Pet faces is to convince regulators to approve a the chickens naturally made IgY against the cat dual approach today. She plans to recommend vaccine that doesn’t directly improve the cat’s protein, which was transferred to their eggs. it to patients and cat-sensitive members of her welfare. In the United States, a direct benefit The company provided egg powder loaded family, too. “It’s worth a try,” she says. Perhaps to the cat is not a requirement, but in the with these anti-Fel d 1 antibodies, and Purina this, or other options, might one day mean European Union it is. Bachmann is speaking coated its pet food with it. cat lovers don’t have to choose between their to authorities in both territories. More than two dozen cats that ate the food feline and human loved ones. He also thinks that the vaccine could be for six months appeared totally normal, when used in people, and he tried an early version7 subjected to a battery of behavioural tests8. In Amber Dance is a freelance science journalist on himself, with benefits for his cat allergies. another study of 105 domestic shorthair cats9, in Los Angeles, California.

He hopes to bring the vaccine to human clinical it took about 3 weeks for the diet to have an 1. Gergen, P. J. et al. J. Allergy Clin. Immunol. Pract. 6, trials soon, along with another using the same effect on Fel d 1, eventually reducing the con- 101–107 (2018). approach against peanut allergy. He is also centration in hair and fur by an average of 47%. 2. Couroux, P., Patel, D., Armstrong, K., Larche, M. & Hafner, R. P. Clin. Exp. Allergy 45, 974–981 (2015). thinking about generating hypoallergenic dogs, That might not be enough to help the 3. Ellis, A. K. et al. J. Allergy Clin. Immunol. 140, 486–496 although multi-component vaccines would be most-sensitive allergy sufferers, says Gawchik, (2017). 4. Orengo, J. M. et al. Nature Commun. 9, 1421 (2018). required to cover their multiple allergens. but it could make a difference for some. In an 5. Thoms, F. et al. J. Allergy Clin. Immunol. 144, 193–203 as-yet-unpublished study, researchers at Wash- (2019). Tasty solution ington University in St Louis found that people 6. Thoms, F. et al. Viruses 12, 288 (2020). 7. Schmitz, N. et al. J. Exp. Med. 206, 1941–1955 (2009). Just as Regeneron is exploring the possibility with a cat allergy had fewer symptoms when 8. Matulka, R. A., Thompson, L. & Corley, D. Front. Vet. Sci. 6, of delivering antibodies directly to patients, exposed to skin flakes and fur from cats eating 477 (2020). 9. Satyaraj, E., Gardner, C., Filipi, I., Cramer, K. & Sherrill, S. some are taking a similar approach to dealing the special food than when exposed to skin and Immun. Inflamm. Dis. 7, 68–73 (2019). with Fel d 1 in the cats themselves. Pet-food fur from cats eating a control diet. 10. Griffith, I. J. et al. Gene 113, 263–268 (1992).