
AsianScientist (Jun. 15, 2017) – Antibodies are abundant in our blood—every milliliter contains about ten milligrams of these highly efficient proteins, which help our bodies fight off infections. But what you might not know is that antibodies have also been used as drugs to treat infectious diseases since 1891, when Emil von Behring and Shibasaburo Kitasato discovered that “serum therapy” could prevent and cure diphtheria and tetanus.
Antibody drug development has come a long way since then. Purification methods—important because purified antibody products cause fewer side effects compared to whole serum—are now more effective at separating antibodies from other proteins and soluble factors in the blood. Scientists today are also able to use genetic information from antibody-producing cells to generate antibodies in cell lines that have been optimized for protein production.
A recombinant revolution
This technique, known as recombinant protein technology, has truly revolutionized antibody drug development. Monoclonal antibodies (mAbs)—recombinant antibodies produced from the genetic material of a single antibody-producing cell—can be easily produced at industrial scale. This means that the exact same antibody can be produced over and over again, which is essential for ensuring quality control, consistency and safety for the patient.
Such antibodies can be used to treat victims with a high likelihood of rabies or tetanus exposure. While there is an effective, licensed vaccine for rabies, the cost is sometimes prohibitive for those in poorer countries where rabies may be prevalent. Antibodies are an obvious alternative. Globally, three candidate mAbs are in phase II testing for rabies; a fourth, RMAb or Rabishield, produced by the Serum Institute of India in partnership with MassBiologics, was launched in India in 2016.
In contrast to mAbs, the polyclonal pool of antibodies in antiserum is produced from thousands of different antibody-producing cells, making each batch of antiserum unique. Polyclonal human- or animal-derived antibody products are very efficient and can be used to prevent or treat a broad range of infectious diseases, such as cytomegalovirus (CMV) and hepatitis B virus (HBV) infections, Clostridium botulinum infections in infants, and respiratory syncytial virus (RSV) infection in high-risk infants.
Vaccines or antibodies?
There are, however, still a number of infections for which vaccines and specific treatments are not available. In such cases, antibodies may be the only treatment option. This was the case during the recent global Ebola outbreak, where a cocktail of three mAbs, known as ZMapp, was used experimentally to treat infected healthcare workers returning from outbreak areas.
The exceptional severity of the Ebola infection left physicians with little choice but to use antibodies that had only ever been tested in animals. While the patients survived, there is no concrete proof of the antibodies’ efficacy in curing Ebola in humans. The clinical trial for ZMapp could only be started at the end of the Ebola outbreak in Liberia, and was eventually halted because no new patients could be recruited.
What is the current price for a dose of an antibody drug? Polyclonal antibodies acquired via the Pan American Health Organization (PAHO) Revolving Fund cost between US$10-110 per dose, depending on how easy it is to acquire the antiserum from humans. For example, anti-tetanus serum is relatively easy to come by because most people in developed countries are vaccinated, compared to rabies where few people have immunity. Antibody drugs to treat cancer or autoimmune diseases might run into the thousands of dollars.
In light of this, vaccines are the more cost-effective option, and antibody drugs only make sense as a treatment option when no vaccine is available. Yet, interestingly, while the tetanus vaccine costs almost nothing and vaccination coverage is extensive, there is still substantial demand for a polyclonal anti-tetanus antibody. This means that even though a vaccine is widely used, there are still people who might not respond well to it, or those for whom protection has waned over the years.
Dengue: an antibody-based assault
Where does dengue stand in the equation? A complicated disease, dengue has four serotypes which behave like individual viruses: each can cause illness despite previous infection with another serotype.
Dengvaxia, the vaccine recently commercialized by Sanofi Pasteur, is not recommended for certain at-risk population groups—children below nine years of age and adults above 45 years of age. Its efficacy is also more limited if the recipient has never been infected with dengue before.
Even if additional dengue vaccines become available in the near future, vaccination might not be possible for everyone: mass vaccination initiatives will take time, and not everybody will respond well. This builds a strong case for developing an mAb for dengue.
At the Agency for Science, Technology and Research (A*STAR), our team at the Singapore Immunology Network (SIgN) has identified a new human antibody that is highly effective at neutralizing the activity of all four dengue virus serotypes. In collaboration with Chugai Pharmabody Research Pte Ltd (CPR), a research centre of Chugai Pharmaceutical Co in Singapore, we have optimized the antibody and are in the midst of developing it into a treatment for dengue, with funding from a US$5.3 million grant administered by the Global Health Innovative Technology Fund (GHIT Fund).
I have been asked many times whether the time, expense and effort spent developing a dengue antibody is truly worth it. After all, most severe dengue cases can be treated in the hospital with close observation and careful fluid resuscitation. Fatalities are therefore relatively rare—fewer than 0.1 percent of cases.
In the era of modern medicine, however, we should be looking beyond fatalities, and placing a greater priority on patient welfare and wellbeing. A dengue infection is often painful and debilitating, and can take a great toll on the body. My collaborators and I aspire to develop a safe drug that can reduce the severity of dengue infection and shorten the length of the disease, for the benefit of patients and their caregivers.
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Copyright: Asian Scientist Magazine; Photo: Shutterstock.
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