Monoclonal antibody treatments have many challenges — Narval is fixing them

Monoclonal antibodies are the building blocks of some of the most important medical treatments in the world. But they have limitations. For example, the large size of the molecules mean monoclonal antibody treatments usually need to be injected — even for eye conditions. Narval CEO Jose Luis Nuno describes the first time he saw a patient get injected in the eye to treat diabetic retinopathy, a condition that can lead to blindness. “It costs $2,000 every month, you need to get one per month, so it’s very expensive, very difficult and of course painful to be injected there,” he said. “That’s the problem with antibody drugs.”

Conventional antibodies also have other limitations. They are expensive to manufacture and need to be kept refrigerated, causing challenges in areas without cold chain supply infrastructure. Narval is tackling these problems by developing antibody drugs using synthetic antibody mimetic proteins (AMP), which are 40 times smaller than monoclonal antibodies but have the same biological functions. The biotech is pitching today at TechCrunch Disrupt’s Startup Battlefield and is about to kick off raising for its seed round.

Narval licenses its platform to pharmaceutical companies and uses generative AI to design AMP candidates to treat different diseases. The AMPs are meant to replace monoclonal antibodies for use in new first-in-class therapeutics. It is currently closing its first two pharmaceutical customers for the development of two of its AMP treatment candidates.

Narval’s origin story

Narval’s team currently has four different patents, including three that have already been published and one submitted in the United States, the European Union, China, India and Mexico. The company was founded by Jose Luis Nuno, chief scientific officer Alejandro Nuno, and academic co-founder Alexei Licea. This is the third biotech startup that Jose and Alejandro, who have known each other for 17 years, have worked on together. At their first startup, they developed a pharmaceutical product that increased the efficiency of vaccinations in poultry and swine. It was launched in 14 countries in partnership with German pharma Boehringer Ingelheim.

Then at their last startup, Y Combinator alum Unima, they spent six years developing a new diagnostic technology using antibodies from sharks, called variable new antigen receptors (VNAR), which evolved into Narval’s underlying technology for AMPs.

“We saw that these shark antibodies have the potential to be used not only for diagnostics, but also for therapeutics because they are capable of doing things that conventional antibodies cannot do because they are really resistant to environmental conditions, for example,” said Jose. “They are resistant to heat and they can be manufactured at a much lower close than monoclonal antibodies.”

Licea found a way to make shark antibodies even smaller and more resistant, resulting in the creation of AMPs. To do this, he took the part of the shark antibody, called CDR3, that recognizes viruses or proteins that need to be neutralized and fused it to a synthetic scaffold protein from a sea snail. This is why the Narval team was able to create AMPs that are 40 times smaller than monoclonal antibodies and that can cross tissue barriers in a way that conventional antibodies can’t. This means they can be administered to a patient through nasal sprays, eye drops (no more eye injections), oral medicine and even transdermal patches.

Another challenge Narval is solving is the logistical challenge of transporting monoclonal antibodies, which need to be stored in a freezer. Once they are removed from freezing temperatures, they immediately start losing efficacy. Jose said AMPs are hardier than conventional antibodies. Since they don’t need cold chain logistics, they can be delivered to remote locations, hot areas without access to freezer storage, and places without hospitals.

Some potential use cases for AMPs include treating pediatric diseases with AMP through inhalers or topical application. For conditions like diabetic retinopathy, treatment can be applied in eye drops, instead of injection into the eyeball. Another example is treating IBS through an oral tablet, getting AMPs directly into the digestive system instead of the more roundabout route that an injection would take. Jose said it can even be used to treat diseases in animals, like cancer in dogs and cats.


Designing and optimizing AMPs at scale

Narval is able to design AMP candidates for pharmaceutical clients at scale using generative AI. The startup says hundreds of AMP variants can be designed and evaluated to select a cluster of the best candidates in only a few hours and with minimum human interaction. The first step of the process is to identify what the AMP is supposed to neutralize — for example, the flu virus. Then Narval’s platform selects the best VNARs from its library of shark antibodies, before generating several copies of different VNAR structures.

Narval’s software determines which AMP has the best affinity for the target it is supposed to neutralize. Then the platform uses AI algorithms to generate changes in its structure, creating several better versions of the AMP. The process is repeated, and once it has the optimal version of the AMP, it is chemically synthesized and licensed to the pharmaceutical company, which performs clinical trials.

The company has three validated AMP treatment candidates that will enter preclinical testing by the final quarter of this year. Its lead candidate is for diabetic retinopathy, and the company already tested it in animals, confirming that it can be administered through eye drops and decreases the development of blindness. The second AMP candidate is for ocular inflammation and is also meant to replace eye injections with eye drops. The third candidate are AMPs that are designed to neutralize the SARS-CoV-2 virus through an inhaler.

“We already know that the molecule works for treatment, but the next step is to go into preclinical testing that will allow us to be able to apply for an [investigational new drug application] with the FDA and then move onto first testing on humans,” said Jose. “The goal is to have all the preclinical results by the second quarter of next year and start the application from mid-2024 and move to clinical phase by the end of next year.”

Competitive landscape

Jose divided Narval’s competitors into three groups. The first are conventional antibody platforms like Prothena and AbCellera that develop conventional antibody drugs. Others, like Nabla Bio and Absci, use AI to design conventional antibodies and optimize them, but their antibody molecules are still limited by size and shelf stability. Then there is a small group of startups, like AdAlta and MIP Discovery, that are working with synthetic antibodies. But Jose says those companies are still very early stage and have some of the same problems as conventional antibodies, like size.

Narval’s differentiator is that it uses proteins that mimic the activity of an antibody and uses AI not just to optimize a molecule, but also to design it. The generative AI–based process allows Narval to go from a target to a final proposal using thousands of different versions of AMPs, therefore giving them a better chance of designing the best ones for different applications.

The startup plans to start its seed fundraising at the end of this month. It has been operating in stealth since it was founded earlier this year and is launching at TechCrunch Battlefield. Jose said his team aims to raise $3 million in a seed round, which will be used to move at least two of its AMP treatment candidates into preclinical trials. Narval has already received some funding from angel investors, including ones who invested in Unima.

“After having a lot of experience in diagnostics, I think that trying to change the way that antibody drugs are is important not only because of the market opportunity, but because we can change how healthcare can be provided to most of the population,” Jose said. “The first time I saw someone get injected in the eye, it made a big impression on me. To have to pay $2,000 each time to get that shot in the eye, that’s not what we want to do. Our mission has always been to develop technology to increase healthcare for everyone.”