The strategy employs chains of binding agents, like “beads on a string”, which target two sites on one or more pathogenic molecules to neutralize their activity and promote their clearance by the body’s immune system.
The low-cost, easy-to-replicate tool has demonstrated applications against several different toxins, from those found in contaminated food to those used in bioterrorism, and may also prove effective in targeting other types of pathogens.
The research team, based at Tufts University’s Cummings School of Veterinary Medicine, demonstrated the method’s efficacy in preventing the symptoms of botulism, a rare but deadly disease caused by Clostridium botulinum neurotoxin (BoNT), considered one of the most dangerous bioterror threat agents. The findings were presented earlier this year in PLoS ONE.
“Currently, antitoxins are difficult to produce and have a short shelf life, making them very expensive. This new approach provides a low-cost way to develop highly effective antitoxins,” said senior author Charles B. Shoemaker, PhD, professor of biomedical sciences at Tufts University's Cummings School of Veterinary Medicine.
“This method has the potential to target a number of pathogens – not only toxins such as BoNT, but viruses or inflammatory cytokines. It is an important platform through which to address other significant diseases,” says co-author Saul Tzipori, BVSc., DSc, PhD, professor of biomedical sciences and director of the Division of Infectious Diseases at the Cummings School.
Shoemaker and team had earlier found that pools of small ‘tagged’ binding agents were highly effective in targeting toxins, neutralizing their function, and flagging them for removal via the body’s immune system in the presence of an anti-tag monoclonal antibody.
In the newly published in vivo study, the researchers have advanced this approach by linking two BoNT-binding agents together and including two copies of the tag. The binding agents are small, stable proteins derived genetically from unusual antibodies produced by toxin-immune alpacas. The resulting molecule, called a ‘double-tagged heterodimer,’ binds to two separate sites on the toxin. Binding of this single heterodimeric agent much more effectively neutralizes the toxin than the unlinked monomer binding agents used in the prior research. In addition, attaching two tags to each of the two linked agents leads to toxin decoration by up to four anti-tag monoclonal antibodies, which promotes rapid toxin clearance from the blood, the researchers found (see figure).
The double-tagged heterodimer antitoxin agent strategy was shown to be efficacious against two types of BoNT in the PLoS ONE report. The antitoxin agents were administered at the time of exposure, or shortly after. Treated mice did not show any symptoms of botulism – including the lethal paralysis which characterizes the disease, even when exposed to high toxin doses. Thus, the benefits of complex antitoxins were equaled or bettered by administration of two easy-to-produce agents; a heterodimer binding agent and an anti-tag monoclonal antibody.
According to Shoemaker, a major advantage of this approach is that, unlike treatments that only neutralize toxins, this treatment both neutralizes toxins and ensures their rapid clearance from the body. “Agents that only neutralize their pathogenic target will eventually dissociate which will allow the pathogen to continue doing damage if it is not eliminated,” he said.
The group has now successfully taken the research further by building longer strings of binding agents that target multiple toxins with a single molecule—for example, the two types of Shiga toxins that are produced by some E. coli found in contaminated foods or the two toxins produced by hospital-acquired C. difficile infections.
The work was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), the Department of Health and Human Services, and the Intramural Research Program of the NIAID.
Additional authors on the paper are co-first authors Jean Mukherjee and Jacqueline M. Tremblay; and Kwasi Ofori, Karen Baldwin, Xiochuan Feng, all in the Department of Biomedical Sciences, and Daniela Bedenice of the Department of Clinical Sciences at the Cummings School. Clinton E. Leysath, of the NIAID, and Robert P. Webb, Patrick M. Wright, and Leonard A. Smith, all of the United States Army Medical Research Institute for Infectious Diseases, also contributed.
Mukherjee J, Tremblay JM, Leysath CE, Ofori K, Baldwin K, et al. “A Novel Strategy for Development of Recombinant Antitoxin Therapeutics Tested in a Mouse Botulism Model.” PLoS ONE 7(1): e29941. Published online January 6, 2012, doi: 10.1371/journal.pone.0029941About the Cummings School of Veterinary Medicine at Tufts University
Attending BIO? Please stop by our booth (#301) to learn more about the innovative work done at the Cummings School, including clinical trials, infectious disease vaccine and therapy research and more.
Thomas Keppeler | Newswise Science News
Inselspital: Fewer CT scans needed after cerebral bleeding
20.03.2019 | Universitätsspital Bern
Building blocks for new medications: the University of Graz is seeking a technology partner
19.03.2019 | Karl-Franzens-Universität Graz
Cancers that display a specific combination of sugars, called T-antigen, are more likely to spread through the body and kill a patient. However, what regulates...
DESY and MPSD scientists create high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might find intriguing applications in petahertz electronics and for spectroscopic studies of novel quantum materials.
The nonlinear process of high-order harmonic generation (HHG) in gases is one of the cornerstones of attosecond science (an attosecond is a billionth of a...
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
26.03.2019 | Physics and Astronomy
26.03.2019 | Earth Sciences
26.03.2019 | Earth Sciences