BIODEFENSE

Through DOR’s BioDefense Division, the company is developing biomedical countermeasures pursuant to the Project BioShield Act of 2004. Specifically, DOR is developing bioengineered vaccines designed to protect against the deadly effects of ricin toxin and botulinum toxin, both of which are considered serious bioterrorism threats.

RiVax™

Regulatory and Development Pathway
DOR is the world leader in ricin toxin vaccine research. RiVax™ is DOR's proprietary vaccine developed to protect against exposure to ricin toxin and the first ricin toxin vaccine ever to be clinically tested in humans. Ricin is a potent glycoprotein toxin derived from beans of castor plants. It can be easily produced, is stable over long periods of time, is toxic by several routes of exposure and thus has the potential to be used as a biological weapon against military and/or civilian targets. There are currently no vaccines available to prevent ricin poisoning or medical treatments to care for poisoning victims. DOR has announced positive Phase I clinical trial results for RiVax™ which demonstrated that the vaccine is well tolerated and induces antibodies in humans that neutralize the ricin toxin. The functional activity of the antibodies was confirmed by animal challenge studies in mice which survived exposure to ricin toxin after being injected with serum samples from the volunteers. The outcome of the study was recently published in the Proceedings of the National Academy of Sciences.

This Phase 1 clinical trial was conducted by Dr. Ellen Vitetta at the University of Texas Southwestern Medical Center at Dallas, DOR's academic partner on the RiVax™ program. The National Institutes of Health has awarded a total of $11.7 million to DOR for the development of RiVax™ covering process development, scale-up and cGMP manufacturing, and preclinical toxicology testing pursuant to the government’s two animal rule.

Stage of U.S. Government Cooperation
In September 2002, DOR BioPharma, Inc. executed an exclusive, worldwide licensing agreement for the rights to an experimental ricin vaccine (RiVax) from the University of Texas Southwestern Medical Center (UT Southwestern). The vaccine, which is being developed in collaboration with UT Southwestern, is a modified subunit of the native ricin toxin which has been genetically engineered to eliminate both its enzymatic activity and its ability to induce vascular leak syndrome (VLS). Complete elimination of both types of toxicity is likely to render this vaccine safe at effective doses and when administered as an intramuscular injection, RiVax induces protective antibody production in mice (Smallshaw et al. 2002. Vaccine. 20:3422-27).

In parallel to the development of this intramuscular vaccine, we are testing a variety of vehicles incorporating RiVax for nasal administration. The rationale for a nasally-administered ricin vaccine are two-fold: a) Convenience in the event that a large number of people require vaccination in a short period of time, and b) ricin toxin can destroy any cells it comes into contact with, increasing the need for protection of exposed mucosal surfaces. Since likely routes of exposure to the toxin include inhalation or ingestion, protecting the mucosal lining of the lungs and gut is important. Preclinical experiments are ongoing to determine whether a nasal formulation is stable and capable of conferring mucosal immunity.

BT-VACC™

Regulatory and Development Pathway
BT -VACC™ is an mucosally admisistered vaccine developed by DOR to protect against exposure to botulinum neurotoxin, a Category A biothreat as defined by the CDC. Botulinum neurotoxin, a protein toxin produced by the bacterium Clostridium botulinum, is the most poisonus natural substance known to man. Exposure by ingestion or by inhalation results in disruption of peripheral nerve function and paralysis. Recent preclinical studies of a bivalent formulation of BT -VACC™ in animals have demonstrated immune responses to botulinum toxin serotypes A and B. The animals were then protected against exposure to each of the native toxin molecules given at 1000 fold the dose that causes lethality.

There are currently no FDA-licensed vaccines against botulinum neurotoxin. BT-VACC™ is currently undergoing preclinical testing at Thomas Jefferson University in Philadelphia, PA, DOR's academic development partner. This research is conducted under a Cooperative Research and Development Agreement with the U.S. Army's Medical Research Institute of Infectious Diseases. DOR has entered into a joint development agreement with Dowpharma, a business unit of The Dow Chemical Company to advance the development BT-VACC™. Under the agreement, Dowpharma will provide process development leading to cGMP production.

Stage of U.S. Government Cooperation
In collaboration with Thomas Jefferson University, DOR BioPharma is developing 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 in the gastrointestinal tract. These truncated derivatives of the heavy chain lack any of the enzymatic functions of the intact molecule and are completely safe. When administered intranasally, the heavy chain of botulinum serotype A elicits a strong neutralizing antibody response and protects against challenge with high doses of botulinum toxin in mice (Parker and Simpson 2003. Infection and Immunity 71(3): 1147-54). DOR BioPharma has an exclusive, worldwide license agreement for the rights to intranasal and oral delivery of botlinum vaccine from Thomas Jefferson University.