Delhi belly. Montezuma’s Revenge. The Aztec two-step. Here in the West, we like to slap whimsical names on traveler’s diarrhea. For those of us blessed with ready access to food and sanitary infrastructure, these diseases are a minor inconvenience.
Those in the developing world are not so lucky: diarrhea kills hundreds of thousands of people each year, most often infants and newborns. Traveler’s diarrhea is also a major concern for antimicrobial resistance. Antibiotic-resistant strains are on the rise, and over-use of antibiotics is thought to encourage the emergence and spread of new ones. Sadly, traditional drug development technologies have largely failed to provide a complete solution, despite decades of investment by big pharma,foundations, and, especially, the US military.
Making a dent will require fresh thinking. Today, Lumen announced a new $14 million research collaboration funded by CARB-X. The goal of this 2.5-year project is to create a low-cost, edible antibody drug cocktail that blocks infection by two of the main causes of travelers’ diarrhea: enterotoxigenic E. coli and campylobacter.
Ultimately, the Lumen-led research coalition aims to wipe out all incarnations of this disease, but we’re starting with these first two pathogens — the ringleaders, if you will. (In future work, we’ll expand the coverage to target other major etiological agents, including norovirus.)
Highlighted below are some of the ways Lumen and its collaborators are bringing fresh thinking to this old fight.
Searching for a solution: historical antecedents and serendipity
The idea for an edible (i.e., orally delivered) antibody drug has been around for a long time: the first modern edible antibody clinical trial was in 1988. For enteric disease in particular, edible antibody drugs have a lot going for them — they can be safer, more effective, and easier to distribute and administer than antibodies delivered by injection.
But for technical reasons, infections turn out to require much larger doses of therapeutic antibodies than other diseases. And oral delivery requires even more since GI passage is, by its nature, transitory. The extremely high cost of making antibody drugs with traditional technologies therefore prevented widespread adoption in the fight against infectious diseases.
At the heart of it, this is the barrier that Lumen’s technology overcomes. The goal of Lumen’s new CARB-X project is a radical new incarnation of this old idea: an edible antibody drug cocktail that is cheap enough for charitable distribution at vast scale to the neediest populations in the developing world.
The modern rebirth of this idea can be traced back to a DARPA program officer named Dan Wattendorf, who launched DARPA’s biotechnology division in 2010. Dan had the insight that antibody drugs could be used to fend off a pandemic. This idea is now, unfortunately, familiar to most because of the Covid-19 pandemic. At the time, however, it was unconventional, due to the slow pace of development and well-known cost and scalability issues associated with antibody drugs. In pursuit of that goal, Dan’s group successfully accelerated the development process, laying the foundation for the AbCellera/Lilly Covid-19 antibody drug that reported encouraging efficacy data in clinical trials and subsequently received FDA emergency use approval. But less progress has been made at solving the cost and scalability issues, which sadly the slow rollout of these Covid-19 antibody drugs has also shown.
After DARPA, Dan made his way to the Gates Foundation, where he leads the Innovative Technology Solutions team. There, he continued working on the problem of making antibody drugs in a more rapid and scalable manner. It was this effort that led Dan’s team (ably spearheaded by his colleague Omar Vandal) to Lumen Bio, just 10 weeks after we incorporated.
Unbeknownst to us, Omar was then wrapping up a global search for the best next-generation technology for what most experts thought to be an impossible task: manufacturing huge quantities of antibodies for oral delivery at a miniscule cost.
By chance, Lumen had developed exactly the technology needed to accomplish this goal. In a preprint just released on bioRxiv we describe exactly how this is accomplished, so we won’t reprise all that data here. In short, though, the proof-of-concept product — a single antibody directed at preventing infection by the most common strain of C. jejuni — completed its first clinical trial last year (NCT04098263), and is heading toward a proof-of-concept efficacy study this spring, Covid-19 permitting. Remarkable progress from a standing start just two years ago, including the commissioning of a large (>2,000-liter) cGMP production facility at Lumen’s lab in Fremont.
The CARB-X program builds on this strong foundation, and in doing so advances the state of the art to a new level: high-complexity antibody cocktails.
Fighting complexity with complexity
Antibody drugs are a remarkable accomplishment of late 20th century biotechnology: broadly reactive as a class, yet individually possessing exquisite specificity. In general, this allows for high-potency drugs with fewer toxicity risks than small-molecule pharmaceuticals.
But this specificity has a downside. Rapidly evolving viruses and bacteria may develop small mutations that prevent a highly specific single antibody drug from binding and neutralizing them. Consider Regeneron’s Covid-19 drug, in the news recently when it was administered to President Trump. To reduce the odds of evolutionary escape, Regeneron made a “cocktail” of two antibodies that bind to the virus in different locations. This reduces the chance of evolutionary escape compared to single antibody drugs like the AbCellera/Lilly product.
Turning back to our CARB-X project, the challenge is vastly more complicated. The virus that causes Covid-19, SARS-CoV-2, is a single pathogen that has been circulating (and evolving) in humans for just over a year. By contrast, Lumen is wrestling with not one but two pathogens in the CARB-X project — and they have been circulating (and evolving) in humans for decades, if not centuries. Tackling this breadth of genotypic diversity is much harder.
Based on data compiled by our collaborators, we believe that an antibody cocktail that blocks most of the disease-causing bacteria will require 12–20 antibodies. Ensuring that we end up at the low end of that range is why we recruited our colleagues at A-Alpha Bio, the Naval Medical Research Center, and Tufts University to join us. This is an unprecedented challenge, particularly when you consider that until late last year, the FDA had yet to approve anything with more than a single antibody in it!
It would be extremely difficult to construct a safe cocktail product using traditional injected antibodies. Once injected, antibodies eventually permeate nearly every tissue in the body. That means there’s a good chance they might unexpectedly bind to something they’re not supposed to, with disastrous consequences for the patient. Traditional injected antibody drugs routinely fail in clinical trials due to this kind of unexpected toxicity. For example, Lilly’s Covid‑19 antibody trial was put on hold at one point over such safety concerns. Increasing the number of antibodies in a cocktail increases the risk that one of them might accidentally cause such mischief.
Orally consumed antibodies like Lumen’s are far safer. An antibody is a protein, and like the countless other proteins we consume every day, they are generally too large to reach systemic circulation. This drastically lowers the risk of harmful side effects. (As a bonus, we also expect to see enhanced efficacy in GI diseases like traveler’s diarrhea and C. difficile infection: the same barrier tissues that prevent orally consumed antibodies from escaping the GI tract make it difficult for injected antibodies to reach the site of disease.)
Edible antibodies: how solving the cost and scaling problem brings it all together
Delivering antibody drugs orally rather than by injection makes them safer but creates another problem: high cost. Orally delivered antibodies require repeat dosing, and antibodies made with traditional technologies (e.g., CHO cell fermentation), which typically cost $100-$200 per gram, are too expensive to manufacture in the quantities necessary for oral delivery. This is the challenge that led the Gates Foundation team to discover Lumen in the first place, after all, and despite decades of efforts by various well-funded groups, no one had found a solution.
It is striking that edible antibody drugs have been too expensive even for treating enteric diseases that are major cost-drivers in the rich world, such as C. difficileinfection. When made with traditional platforms, edible antibody drugs are simply far too expensive for health care systems to afford, even in the West. And that’s saying something given the eye-popping prices on some recent new drug launches.
We are intent on shattering that cost barrier. Lumen aims to make a product that is — in the words of Dan and Omar — “dirt cheap.”
We aim to create a product that can meet the needs of all our potential customers — from the developing world infants whose lives can be saved, to developed world travelers who’d prefer not to have their beach vacation interrupted by a bout with Montezuma.
Brian Finrow is cofounder and CEO of Lumen Bioscience; Jim Roberts is Lumen’s cofounder and Chief Scientific Officer.