Observing the streets of Buenos Aires City reveals a burgeoning culinary trend: a proliferation of establishments dedicated to a diverse array of hamburgers, encompassing smash burgers, sliders, gourmet combinations, and even the notorious raw burger. While many Argentines are embracing this newfound enthusiasm for ground beef, for parents of young children, the trend presents a considerable challenge. And not solely due to concerns regarding junk food and obesity. The primary source of apprehension is that hamburger meat is identified as the principal agent behind a potentially life-threatening condition known as haemolytic uraemic syndrome, which poses significant risks, particularly to children under the age of five. The disease originates from bacteria present in cattle and is transmitted through contaminated food, particularly undercooked ground beef. This bacteria, known as Escherichia coli, is frequently located in the intestinal tract of cattle and generates a toxin, referred to as Shiga, which results in diarrhoea, often bloody, along with abdominal pain and fever, and has the potential to cause irreversible kidney damage. Argentina exhibits the highest prevalence of HUS globally, with approximately 300 children diagnosed with the condition annually, as stated by biologist Vanesa Zylberman, who serves as the research and development manager and technical director at the Argentine biotechnology firm Inmunova. “There is no specific treatment for HUS today,” Zylberman tells. “All that can be done is supportive care.” The unusually high incidence of HUS in Argentina serves as a significant factor for Inmunova’s decision to concentrate on developing what may potentially be the world’s first specific treatment for the disease. Its investigational drug, INM004, is currently undergoing Phase 3 clinical trials, the final stage of testing prior to the company seeking regulatory approval. The international trial encompasses 220 children aged between nine months and 18 years and is being carried out across more than 40 health centers in Argentina and Europe.
Contamination with Shiga toxin–producing Escherichia coli can arise not solely from meat but also from various food items or water tainted with faecal matter, encompassing vegetables and fruit. However, minced beef presents specific challenges, as bacteria present on the surface of a cut of meat can become distributed throughout the entire product during the grinding process. “That’s why in many parts of the world it is known as hamburger disease,” Zylberman explains. Argentina’s elevated incidence cannot be ascribed to a singular cause, she asserts. The outcome is attributable to a confluence of factors, encompassing dietary practices, the substantial cattle population within the nation, various bacterial strains, and prevailing environmental conditions. “We eat a lot of meat, there are a lot of cattle, and sometimes there’s a lack of control over certain types of consumption.” Cases tend to rise during the summer months, a period when numerous Argentines are travelling and dining in establishments where food-handling standards may differ. Importantly, the approximately 300 annual cases of HUS constitute merely a small portion of STEC infections. Zylberman estimates that approximately 90% of individuals who contract the bacteria do not progress to develop the disease, frequently experiencing spontaneous recovery. Some infections remain undiagnosed due to their presentation of mild or negligible symptoms. However, when it does occur, HUS can pose significant risks, particularly for children. Zylberman emphasises that the disease is the primary reason for kidney transplants among adolescents.
The initial manifestations of a STEC infection commence in the gastrointestinal tract, generally becoming evident 3 to 4 days following the ingestion of the bacteria. Initially, one may experience significant abdominal discomfort, characterised by acute cramps that can manifest as sharp, twisting sensations. This is followed by diarrhoea, which typically begins as watery but progresses to bloody within 24 hours. Numerous individuals encounter recurrent episodes of vomiting and nausea, complicating the maintenance of adequate fluid intake. This is typically associated with either the absence of fever or the presence of a very low-grade, mild fever. The primary concern, as noted by medical professionals, is the absence of urination, particularly if this symptom arises while diarrhoea appears to be subsiding. It indicates that the infection is progressing to haemolytic uremic syndrome and that renal function is deteriorating. HUS primarily impacts small children due to the ongoing development of their immune systems, according to Zylberman. There exists a more intricate explanation: the kidneys of children possess a greater concentration of receptors that draw in the Shiga toxin, the harmful agent responsible for internal damage. This is the rationale behind the increased severity of the damage. Furthermore, the severity of diarrhoea associated with the disease leads to a more rapid dehydration of their bodies. When a small body depletes its fluids, there is a reduction in blood flow to the kidneys, which exacerbates the difficulty for these organs to recuperate. This devastation underscores why HUS is regarded as a critical public health crisis, even though it impacts a relatively small segment of the population. Currently, all that can be done when a child becomes ill with the disease is to provide supportive care, according to the expert. Around 40% to 50% of patients necessitate dialysis during the acute phase, whereas long-term complications may encompass chronic kidney disease, hypertension, and neurological damage. Inmunova projects that the disease may result in fatality in roughly 3% of instances.
One of the reasons HUS has proven to be particularly challenging to treat is that physicians are unable to employ antibiotics to eliminate the bacteria, which is the conventional remedy. This is because, regarding STECs, rather than eliminating the bacteria, the drug induces stress, leading them to release an increased amount of toxin. That prompted the researchers at Inmunova to pursue an alternative approach: an antitoxin. INM004 is a biological drug composed of polyclonal antibodies that target the Shiga toxin. The antibodies are designed to bind to the toxin prior to its attachment to receptors on kidney cells, thereby disrupting the sequence of events that leads to severe disease. The concept has been the subject of scrutiny for years. Zylberman has been engaged in antitoxin research since her doctoral studies. The breakthrough emerged from advancements in protein engineering: researchers crafted a unique molecule that integrates a segment of the Shiga toxin with an additional molecule that enhances its stability. This engineered molecule is subsequently injected into horses, prompting their immune systems to generate antibodies against the Shiga toxin, effectively transforming them into a type of “biological antibody factory,” as noted by Zylberman. The scientist underscores that the animals – selected for their ability to produce a significant proportion of antibodies – “do not suffer and don’t develop the disease or symptoms.” And “It is as if they were receiving another vaccine as part of their vaccination schedule,” she explains. The resulting antibodies are subsequently extracted and subjected to a biotechnology process to yield the medication. Inmunova has developed the engineered molecule within its own laboratory and possesses two patents pertaining to the technology. The company collaborates with the Argentine Biological Institute S.A.I.C. (BIOL, in Spanish), a private laboratory engaged in the production of antivenoms and other antibody-based products, to immunise horses and process the antibodies.
The treatment initially needed to undergo preclinical testing, which involved animal models, prior to the commencement of human trials. Phase 1 assessed the safety profile in healthy adult volunteers. Phase 2 was conducted in children diagnosed with HUS, focusing on the ongoing assessment of safety while initiating the collection of evidence pertaining to efficacy. The preliminary clinical studies have indicated promising signs that INM004 may mitigate the renal damage induced by Shiga toxin, although its effectiveness remains to be conclusively established. The outcomes of the preliminary clinical investigations were disseminated in the British Journal of Clinical Pharmacology and Paediatric Nephrology. Now arrives the critical examination. The Phase 3 study is characterised by its randomised and double-blind design. All participants receive the standard supportive treatment they require, while roughly half are also randomly assigned to receive INM004. While Inmunova will only be able to ascertain the efficacy of the treatment at the conclusion of Phase 3 – which is anticipated to extend for another year – there are grounds for optimism: an independent evaluation conducted approximately midway through the trial concluded that the study should proceed. “One thing that has to be highlighted is that this is a development that began in a 100% Argentine company, from the creation of the molecule to its intellectual property,” Zylberman says. “Reaching Phase 3 today is very significant.”
If the final phase proceeds successfully, there will remain regulatory obstacles to navigate prior to the treatment’s availability. The project has secured approval from Argentina’s National Administration of Medicines, Food and Medical Technology, the European Medicines Agency, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency. The EMA and the United States’ Food and Drug Administration have granted INM004 orphan-drug designation, a regulatory status assigned to a medicine under development for a rare disease or condition. However, these agencies will need to evaluate the evidence regarding safety and efficacy after the completion of Phase 3 before making a determination on the approval of the treatment. There is, consequently, no verified timeline for market release. Zylberman details that, if and when that occurs, the treatment will be sold to hospitals and not to private patients, as it will have to be administered intravenously by doctors as part of a larger medical treatment. Currently, Argentina stands as the nation with the highest incidence of HUS globally, while simultaneously being the location where an experimental treatment has made the most significant progress in tackling this issue. Parents ought to maintain vigilance, especially by steering clear of undercooked ground meat for young children. The emergence of a specific treatment marks a notable shift for a disease that has been managed solely through supportive care since its identification in 1955.
