Building antibodies to stop threats

Understanding why some antibodies work better than others, and then improving them. That is the deceptively simple concept driving the work of Luca Varani, Group Leader at the Bellinzona-based Institute for Research in Biomedicine (IRB), which is affiliated to Università della Svizzera italiana (USI). 'We try to understand what makes an antibody effective against a specific pathogen," he explains. "And we use this information to design new, more specific and targeted molecules or antibodies."

Below is an in-depth feature produced by the IRB, in collaboration with laRegione.

Originally from Varese, Luca Varani trained in Milan, Cambridge, and Stanford before joining the IRB in 2007, where he now leads a research group focused primarily on viruses and strategies to counteract them. The starting point of his work is a premise that has become increasingly evident in recent years: antibodies are not just natural tools of the immune system, but also one of the most promising therapeutic platforms in modern medicine. "Six of the ten best-selling drugs in the world today are antibody-based," he says. The main reason is their precision. Unlike many traditional therapies, antibodies hit highly specific targets, reducing side effects. "Chemotherapy, for example, is very powerful but also aggressive and indiscriminate: it attacks cancer cells but also healthy ones. Antibodies, on the other hand, act in a much more targeted way."

Natural but enhanced molecules
Antibodies, Varani emphasises, are molecules that are already naturally present in our bodies. "We are not introducing something completely foreign into the body; we are using molecules that are already part of the human immune system." However, his group goes a step further by engineering these molecules to boost their efficacy. In practice, the researchers isolate natural antibodies from patients who have recovered from an infection, study their structures, and then optimise them to enhance their therapeutic power.

Varani shares a very simple example to explain the principle. When someone catches chickenpox as a child, in most cases they never fall ill from it again. This happens because the immune system produces antibodies that can recognise the virus in the future and rapidly block it. "The blood of a recovered person already contains the molecules that defeated the disease," he explains. One possible strategy, therefore, is to isolate these antibodies and transfer them to another patient. This is the principle of passive immunisation. But the IRB's work goes further. "We take these natural antibodies and try to improve them," says Varani. "We want to understand what really works and how to make the response even more effective."

Stopping the virus's engine
To explain how antibodies are designed, Varani—a fan of engines and racing simulators—uses the analogy of a car. "An antibody can bind to a virus without actually managing to stop it," he explains. "It is like trying to stop a car's motion by hitting its roof: the car will keep moving. To truly stop it, you have to aim for the engine and the wheels." Similarly, his research group's work involves identifying the underlying mechanisms of how a virus functions, its "engine": the parts that cannot change without compromising the survival of the virus itself. This aspect is crucial because many viruses mutate rapidly to evade the immune system. "We saw this with Covid, but it also applies to influenza or HIV," Varani observes. "Viruses change constantly to avoid being recognised." For this reason, the IRB group seeks to design antibodies targeting regions the virus cannot readily modify. "Returning to the car analogy, the engine is always needed. If you can hit that, the virus can no longer function."

From the board to the computer
Antibody design combines biology, structural chemistry and computational simulations. Once the most promising targets have been identified, researchers design potential modifications to the antibody and verify them through computer simulations. "We simulate the behaviour of every single atom in the molecule over time," says Varani. "The computer tells us whether the structure we imagined is likely to be stable or not." But the computer alone is not enough. "Computers always give an answer," he notes with a smile. "The problem is understanding whether it is the right one." After the virtual phase, the molecules must be physically produced in the laboratory and tested against actual viruses. The Bellinzona group focuses primarily on viruses that pose particularly difficult challenges, such as those that can evolve rapidly and develop resistance. The goal is to create antibodies that remain effective even when the virus changes.

The long road to patients
Turning a scientific discovery into a real treatment, however, is a long and expensive journey. Varani sums up the issue with a joke: "The distance between the laboratory and the patient is about 600 million francs." After the initial discovery, you have to manufacture the molecules on a large scale, verify their safety, obtain authorisation from regulatory authorities and go through years of clinical trials. The first phase primarily serves to demonstrate that the treatment is non-toxic. Only later do they move on to larger studies to verify its actual efficacy in patients. "In the pharmaceutical sector, over 80–90% of drug candidates never reach the market," he explains. This is also why Varani places so much emphasis on basic research. "We need to understand the fundamental mechanisms even before we know what concrete application they will have." To illustrate the concept, he cites a historical example: the discovery of DNA's double-helix structure. "When Watson and Crick described the double helix, that discovery seemed almost abstract. But without that knowledge, we wouldn't have genetic medicine or many of today's modern therapies."

Science, creativity and failure
Another theme that frequently recurs in Varani's account is the relationship between science and creativity. "Research is very frustrating," he says. "We are trying to do things that nobody has ever done before, so failure is normal." For this reason, he explains, it is vital to maintain curiosity and motivation even when experiments do not work. "If you don't truly love what you do, you won't last." Outside the laboratory, he pursues very different passions: sports, cycling and racing simulators. Since the 1990s, he has organised online Formula One simulation tournaments featuring professional drivers and enthusiasts from around the world. "I always joke that my publication with the highest impact factor was in Gazzetta dello Sport," he says with a laugh. Behind the irony, however, lies a very serious conviction: scientific research requires time, freedom and the opportunity to explore ideas that might initially seem useless or too risky. It is precisely in these spaces of uncertainty, according to Varani, that the innovations capable of truly changing how we treat diseases are born.