ON 21 January 1925, Dr Curtis Welch sent out a frantic telegram: the children of Nome were dying. The isolated Alaskan village was facing a catastrophic epidemic of diphtheria. More than 20 children were ailing, and dozens more had been exposed. The only hope was diphtheria antitoxin serum, an antibody-rich fluid that could cure the sick and halt the spread of the disease. But Alaska was in the grip of severe winter storms and the nearest serum lay more than 1000 kilometres away across wild terrain that could only be traversed by dog sled.
As news of the crisis spread, all eyes turned north, transfixed by the unfolding drama of what would later be called the Great Serum Race. Newspapers gave daily accounts of the relay as the antitoxin passed from one dog sled team to the next through blinding snow in temperatures that fell to -53 掳C. At last, on 2 February, musher Gunnar Kaasen and his exhausted team delivered the serum to Welch. Nome was saved and Kaasen鈥檚 lead dog Balto became a national hero.
The serum race is an amazing and inspiring story, but perhaps just as amazing is the fact that in 1925, almost 20 years before the discovery of penicillin and well before a vaccine was widely available, doctors had a cure for diphtheria. This struck antitoxin researcher Brent Iverson of the University of Texas, Austin, as he and his daughter were watching the 1995 film Balto, an animated movie based on the race. 鈥淲hen I heard 鈥榓ntitoxin鈥� I had to rewind the tape to be sure I got it right,鈥� he remembers. 鈥淭hat, for me, was a real 鈥榖ack to the future鈥� moment.鈥�
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Iverson鈥檚 surprise is down to the fact that serum therapy, all but forgotten by medical science, is making a spectacular comeback. Originally abandoned when effective antibiotics became available, serum therapy has been transformed by major technological advances over the past three decades. Researchers can engineer antibodies, the active ingredients in serum, to make the therapy much less toxic and more effective than it once was, and such antibodies are now being developed by biotechnology companies. Faced with the rise of antibiotic-resistant bacteria and the threat of new diseases or perhaps bioterrorism, many believe serum therapy鈥檚 time has finally come.
In the pre-antibiotic era, doctors successfully used serum therapy to combat big killers such as pneumonia and meningitis. The basic idea is simple: infect an animal with a disease-causing organism so that a subset of the animal鈥檚 immune cells, its B-lymphocytes, produce antibodies against the infection. You then extract the animal鈥檚 serum 鈥� a cell-free fluid derived from blood 鈥� and inject it into a patient.
Today, we understand the details of this treatment much better. Each B-lymphocyte makes only one particular antibody that recognises and binds to a specific part of a foreign molecule, or antigen. By binding, the antibody sometimes blocks the normal function of the antigen, and also labels the molecule as foreign, telling other components of the immune system to attack. In the case of diphtheria antitoxin, for example, animals infected with diphtheria produce antibodies to parts of the diphtheria toxin, which is responsible for the deadly effects of the disease. When serum from these animals is injected into a patient, the antibodies quickly bind to and neutralise the toxin, giving the patient extra time to mount their own immune response to the infection. This immunity boost can make the difference between life and death.
Dicing with death
In some cases, serum therapy worked as well as antibiotics, but dangerous side effects severely restricted its use. Only a small fraction of the antibodies in serum are the type required, so to get enough of them into patients, doctors had to use whopping amounts of serum. Large doses increase the risk of triggering an immune response to the foreign animal proteins, reducing the serum鈥檚 effectiveness and producing side effects such as fever, skin welts and sometimes anaphylactic shock.
With the development of the cheaper, safer, and more effective antibiotics, the use of serum therapy had declined by the late 1940s and was eventually only used in rare cases, such as making antivenom to snake bites. But in 1975, Georges Kohler and C茅sar Milstein at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, found a way to use mice to mass-produce antibodies derived from a single B-lymphocyte, a discovery that earned them a Nobel prize. It meant that scientists could produce single antibodies, called monoclonal antibodies, to target one specific part of an antigen. Patients could then receive small, potent doses of purified monoclonal antibodies, greatly reducing the risk of harmful side effects.
But many obstacles remained. Some patients still suffered an immune reaction to the foreign mouse antibodies, and the treatment was still difficult to manufacture. Most researchers thought antibody therapy would remain impractical for preventing and treating most infectious diseases.
Cancer researchers, however, had a different outlook. With relatively few effective treatments available, they were open to more unconventional approaches and developed antibodies to target and kill malignant cells. Many technological advances in antibody therapy have come from work on cancer 鈥� of the dozen or so monoclonal antibodies approved by the US Food and Drug Administration (FDA) for use human use, most are cancer therapeutics.
These successes have inspired infectious disease researchers to look again at antibodies. Anthrax researchers, for example, hope to develop monoclonal antibodies that could prevent and treat infection in the event of a bioterror attack. Although an anthrax vaccine already exists, most people will not be immunised unless an attack occurs, which will be too late for the immediate victims. And even with aggressive antibiotic treatment, many people don鈥檛 survive exposure to anthrax. In the letter attacks in the US in 2001, 5 of the 11 who inhaled anthrax died despite antibiotic treatment.
As with diphtheria, anthrax鈥檚 deadly effects are due to a toxin, but the toxin can鈥檛 enter cells without a protein called 鈥減rotective antigen鈥� (PA) that is also produced by the anthrax bacteria. In natural infections, antibodies to PA are important for fighting anthrax. Researchers tried to design mouse monoclonal antibodies to bind specifically to PA, but found they did not stick tightly enough to disrupt it. Iverson, George Georgiou at the University of Texas, Austin, and their colleagues have managed to isolate the antigen-binding fragment of one of the mouse antibodies and engineer it to stick to PA 50 times as strongly as the original antibody. When they injected a stabilised form of the fragment into rats and gave them a huge dose of anthrax toxin 5 minutes later, all the rats survived. All untreated rats died.
Iverson and his collaborators licensed their modified fragment to Elusys Therapeutics, a biotechnology company based in New Jersey. There, Leslie Casey and her colleagues have 鈥渉umanised鈥� the fragment by fusing it to the frame of a human antibody and altering antigen-binding areas to more closely resemble those of a human antibody. In tests on rabbits exposed to spores, all of the animals survived if they received the antibody before exposure. When the team administered the antibody 24, 36 and 48 hours after spore exposure, the survival rates in each case were 80, 50 and 30 per cent. By comparison, all rabbits that did not receive the antibody before or after spore exposure died. Encouraged by these results, Casey plans to test whether the antibody will protect monkeys from anthrax. She is also planning safety trials in humans.
鈥淔aced with the rise of resistant bacteria, many believe serum therapy鈥檚 time has finally come鈥�
Another niche where monoclonal antibody therapy shows great promise is in people who are immunocompromised. They constantly receive antimicrobial drugs to help them fight off infection, yet are unable to do so completely. This makes them walking incubators for multi-drug-resistant pathogens, so more efficient therapies are urgently needed.
Arturo Casadevall and colleague Katerina Dadachova at the Albert Einstein College of Medicine in New York have adapted an approach used in cancer treatments to tackle a particularly problematic fungus that affects AIDS patients. Cryptococcus neoformans causes brain inflammation in 6 to 8 per cent of all patients, and as antifungal drugs are far less effective in immunocompromised patients, these infections are often incurable.
Casadevall and Dadachova began with an antibody that could bind to the fungus but had no antifungal activity of its own. The researchers attached radioactive metal atoms to it (see Graphic), reasoning that the antibody would stick to the fungi and then the radioactive atoms would kill cells 鈥� hopefully fungi 鈥� in the vicinity without damaging the patient鈥檚 tissues too much.
When the team infected mice with C. neoformans and then gave them antibodies 24 hours later, 60 per cent of mice that received the radioactive antibody lived for more than 75 days, and showed no evidence of toxic effects from the radiation. The mice that received non-radioactive antibody were all dead by day 35.
Casadevall believes this type of radioimmunotherapy holds great promise. 鈥淲e鈥檙e trying to get this in clinical trials as soon as possible,鈥� he says. Last year, he and his colleagues showed that a similar approach could work in mice for treating Streptococcus pneumoniae, a bacterium that causes pneumonia and meningitis in both healthy and immunocompromised people and which is becoming increasingly drug-resistant (see Graph). The results suggest this method may have much broader applications. 鈥淵ou are going to see radioimmunotherapy used for some very important infections,鈥� Casadevall predicts.
Emerging diseases are also prompting a great deal of work on antibody therapies. One example is SARS, the often fatal respiratory tract infection that emerged in 2002 and threatened to cause a pandemic. Jan ter Meulen and his colleagues at Dutch biotechnology company Crucell Holland began working on a prophylactic antibody for the disease in 2003.
Rather than trying to humanise a mouse antibody, the team sought to make a fully human one. They mutated antibody-encoding genes isolated from the B-lymphocytes of healthy people who had never been exposed to SARS, and looked among the resulting antibodies for ones that could bind to an inactivated form of the SARS virus. By February 2004, they had found an antibody that stopped the SARS virus replicating and prevented the appearance of symptoms in ferrets when given 24 hours before infection with SARS. Ter Meulen believes this antibody might also have prevented or even treated SARS infections in humans, but the epidemic died down before tests could be done.
Businesses that want to make antibodies for unusual diseases such as SARS face high manufacturing costs and scant hope of huge profits, so most pharma companies shy away from such ventures. This, says Casadevall, is the central sticking point in developing antibody therapies for infectious diseases. 鈥淭he economics favour things like Viagra instead of the life-saving drugs,鈥� he says.
But antibody therapies for infectious diseases can be profitable. One success story is Synagis, a humanised monoclonal antibody produced by Maryland-based MedImmune to combat respiratory syncytial virus (RSV). This respiratory tract infection is common in children under 2, and does not normally cause serious problems. However, high-risk patients such as premature infants or children with chronic lung disease may end up in hospital and can die. RSV causes millions of deaths worldwide each year, and in the US it is estimated to kill 450 every year and put a further 100,000 to 125,000 in hospital.
In large clinical trials, Synagis reduced the severity of disease and the rates of death and hospitalisation in high-risk patients. The FDA has approved it, and the American Academy of Pediatrics recommends using it as a preventive measure in high-risk infants. Doctors start administering Synagis shots to patients before the start of the RSV season in in autumn and continue giving them once a month throughout the season, which lasts 3 to 5 months. Despite the limited market, Synagis is MedImmune鈥檚 top earner. Last year sales reached $942 million, and are expected to top $1 billion this year.
Costly cure
But the flip side is that as with all antibody therapies, Synagis isn鈥檛 cheap. Jose Romero, paediatric infectious disease specialist at the University of Nebraska Medical Center estimates a course of treatment for one baby through a single RSV season costs between $3000 and $5000, and that price means the therapy is cost-effective only for certain high-risk groups. 鈥淭he issue of cost remains a stumbling block,鈥� he says.
Despite these problems, the Synagis success story has inspired researchers like Ian Charles, the CEO of a new UK biotechnology company called ImmunoPrime and professor of molecular biology at University College London. Charles plans to focus on a different market: antibiotic-resistant bacteria. In particular, his company will try to develop antibody therapies for methicillin-resistant Staphylococcus aureus. MRSA is best known as a hospital-acquired 鈥渟uperbug鈥� that infects injuries and surgical wounds, but recently there have been reports of healthy people catching MRSA skin and respiratory infections in the community.
The methicillin-resistant form cropped up back in 1961, but doctors then could still turn to the antibiotic vancomycin when all else failed. But in 1997 partially vancomycin-resistant strains began to appear, and by 2002, fully resistant forms of the bacterium were being reported in the US. With dangerously few new antibiotics in the pipeline, researchers are scrambling to find other ways of fighting it.
鈥淭here are dangerously few new antibiotics in the pipeline鈥�
Charles鈥檚 approach is to identify genes that MRSA needs to survive in the host, and then to search for antibodies that stick to the proteins made by those genes. It may not even be necessary for the antibodies to provoke an immune response in the animal. If it can just interfere with an essential MRSA protein, Charles reasons, that may be enough to inhibit or even halt disease.
ImmunoPrime may face some stiff competition from Elusys, however. Casey says researchers at the company have been working on making therapeutic antibodies for MRSA for some time and claims to have 鈥渞eally interesting results鈥�, but she will not reveal more just yet. Casadevall believes the interest in making antibodies against MRSA is just the beginning of a trend in infectious disease research. With more and more bacteria developing multiple resistance to drugs and few new antibiotics on the way, 鈥渨e are already in a terrible crisis鈥�, he says.
Casadevall believes the end of the antibiotic era is inevitable. 鈥淭he idea of broad-spectrum antibiotics is going to disappear in the 21st century.鈥� When that happens, he says, people will come rushing back to this old idea.
