Capitalising on research, which focused on structure/function relationships of botulinum toxin done by Lance Simpson, the inventor of DOR's oral botulinum toxin vaccine, BT-VACC, DOR has entered into an agreement with Blue Dolphin, a firm specialising in rational drug design, to apply computer-aided design to the discovery of new leads against botulinum toxin.
Under the terms of the agreement, Blue Dolphin will propose novel drug-like inhibitors of the botulinum toxin by targeting a new site on the toxin's structure. Millions of candidate molecules will be modelled for structural and chemical fit to the target site on the toxin using computer aided discovery techniques.
By focusing on the structure of the botulinum toxin, as opposed to derivatives of previously known inhibitors, this "virtual screening" will allow DOR to target new parts of the toxin with new candidate inhibitors.
"I am eager to begin screening drugs utilising new targets in botulinum toxin," said Simpson, "I believe it is essential that we begin the process of finding new post-exposure countermeasures against the botulinum toxin."
The latest research is designed to complement DOR's BT-VACC, oral botulinum toxin vaccine program, which can be formulated as a multivalent, solid oral dosage form. The oral formulation may be sufficiently stable for stockpiling and storage, ideal for rapid distribution and vaccination for military use or civilian vaccination in response to bio-terrorism.
Oral administration of BT-VACC for serotype A produces protective antibodies that afford protection or prolonged survival of treated animals against 30,000 times the lethal dose of botulinum toxin serotype A. Initial studies of BT-VACC for serotype B are ongoing and both the antibody response and protection data are encouraging.
DOR's BT-VACC, oral botulinum toxin vaccine program is attempting to develop a multivalent vaccine consisting of polypeptide fragments of the heavy chain of the botulinum toxin molecule. These fragments retain the domains important for eliciting a protective immune response against the toxin as well as retaining the capacity to bind to epithelial cells in the airways and the gastrointestinal tract.
These truncated derivatives of the heavy chain lack any of the enzymic functions of the intact molecule and are completely safe. When administered intranasally, the heavy chain of the botulinum serotype A elicits a strong neutralising antibody response and protects against challenge with high doses of botulinum toxin in mice.
Development of botulinum toxin countermeasures is a top priority for the US government as they have allocated $1.7 billion (€1.3 billion) to establish and stockpile them under Project Bioshield. The special status of the research undertaken by DOR BioPharma means they also qualify for FDA's abbreviated review process.
Botulinum toxin is an potent neurotoxin synthesised by three strains of bacteria (Clostridium botulinum, Clostridium butyricum and Clostridium beratii). The toxin is known to exist in seven different serotypes, designated A to G, but only three (A, B and E) account for almost all human cases of disease. The Centres for Disease Control and Prevention (CDC) has classified botulinum toxin as a Category A biothreat because of its extreme potency and lethality.
Exposure to botulinum toxin in the nanogram range results in blockage of peripheral nerve function and descending flaccid paralysis ultimately leading to death. Botulinum toxin has been previously used in a number of documented incidents. Subsequent to the 1991 Persian Gulf War, Iraq admitted to the United Nations inspection team to having produced 19,000 litres of concentrated botulinum toxin, with approximately 10,000 litres loaded into military weapons.
Current treatment for botulinum toxin exposure in adults consists of supportive care and post-exposure passive immunization with equine antitoxins. These antitoxins include a bivalent and monovalent antitoxin that consist of neutralising antibodies which are in limited supply from the CDC and have been associated with serious adverse reactions.
Passive immunotherapy with antitoxins is only effective if administered within a narrow window of time post-exposure (18-36 hours) before the onset of symptoms.