PLANET is focusing on the development of therapeutic and preventative drugs in four large, but significantly underserved medical markets:
Planet produced the world's first clinically tested Plantibody, CaroRx™. CaroRx™ binds specifically to Streptococcus mutans, the bacteria that cause tooth decay, and prevents the bacteria from adhering to teeth. CaroRx™ is intended for regular topical preventative administration by both dental hygienists and patients following a thorough cleaning and intervention for any existing decay. CaroRx™ is currently undergoing Phase II U.S. clinical trials under a U.S. FDA-approved Investigational New Drug (IND) application. Clinical trials using CaroRx™ plantibody, funded by Planet and conducted by Planet's collaborators, Drs. Julian Ma and Thomas Lehner at Guy's Hospital, Kings College London, have shown that this treatment can effectively eliminate these decay-causing bacteria for up to two years1-3. Preclinical animal studies4,5 have corroborated the antibacterial effect and decay prevention potential of CaroRx™4,5. PLANET has secured a leading European development and marketing partner for CaroRx™ and plans to create revenues from the sale of this product within 3 years.
How is CaroRx™ Used?
CaroRx™ is designed for use by dentists in a program compatible with the normal 6 month to one year interval for periodic check-up and cleaning. The first step in the use of CaroRx™ is to professionally clean the teeth with a commonly used oral antiseptic to temporarily eradicate both benign and decay-causing bacteria. The antisepsis step is immediately followed by applying CaroRx™ to the teeth several times over a two-week period. No further treatments are required for 6 months to 1 year. In a published clinical trial the Plantibody was compared to the IgG antibody from which it was derived (mouse Guy’s 13 IgG)1. Other controls included a saline solution, and an unrelated antibody also purified from tobacco leaf extract. As can be seen from the figures, bacterial counts return to pre-treatment levels in subjects treated with saline or a non-specific antibody. Subjects treated with the Plantibody SIgA or the original IgG remained free of decay-causing S. mutans bacteria for 6 months:
The optimum dose of both antibody and antiseptic mouthwash and the required duration of application are expected to be determined in planned Phase II clinical trials.
How Does CaroRx™ Work?
The current working hypothesis for the mechanism behind the effectiveness of CaroRx™ is shown below. Many species of bacteria (represented by different shapes and colors) are found on teeth, most of them harmless. Antiseptic treatment kills the S. mutans and many other bacteria. This permits the opening of the "ecological niche" previously occupied by S. mutans. After antisepsis, during CaroRx™ treatment, adhesion of S. mutans to teeth is blocked, while colonization of other oral bacteria occurs unimpeded. After a sufficient period the niche once occupied by S. mutans is occupied by some other organism, or altered in some other way to exclude S. mutans recolonization. At that point no further antibody treatment is needed to exclude S. mutans.
PLANET is developing a new approach for blocking infection by rhinovirus, a major cause of the common cold. Human rhinoviruses account for approximately half of all common colds6 - a significant market opportunity. To infect a human patient, rhinoviruses bind to a specific receptor, called ICAM-1, on the surface of cells in the respiratory tract. Previous work by others demonstrated that by overwhelming the virus with many free soluble copies of this receptor, rhinovirus infection can be significantly impeded7. The typically high cost of producing the free ICAM-1 receptor in conventional mammalian cell culture has prohibited the development of this product by others.
PLANET scientists, seeking to combine the favorable economics of plant-based production and the superior stability of Protected-SIgA™s, fused receptor genes with portions of genes coding for SIgA and produced the resulting fusion protein in plants. In preclinical testing the fusion protein, called RhinoRx™, proved highly protective against cellular damage caused by human rhinovirus infections.
PLANET believes that RhinoRx™ has the potential for significant sales based on the high incidence of upper respiratory infections in both children and adults each year during the fall and spring. In controlled studies, existing cold remedies, such as decongestants, are not effective beyond the first administration. Antibiotics, prescribed with astonishingly high frequency for treatment of colds in the community clinical setting, are completely ineffective.
A Phase I SBIR grant supported the PLANET's initial development activities for RhinoRx™. PLANET has received Phase II SBIR funding of approximately $1.4 million for further development of this plantibody product. In the first quarter of 2005 PLANET plans to complete pre-clinical safety testing and file an IND for Phase I/II clinical trials of RhinoRx™ at the University of Virginia with Fred Hayden, M.D. as Clinical Investigator.
How Does RhinoRx™ Work?
A cold starts when human rhinoviruses attach to nasal epithelial cells through a surface protein called ICAM-1. RhinoRx™ is a fusion of ICAM-1 with a Protected SIgA™, and acts as a decoy, preventing the rhinovirus from attaching to cells (see picture). It is anticipated that RhinoRx™ would be applied as nose drops at the first sign of a cold, or as a preventive when someone suspects that they have been exposed to cold viruses.
Neutralization of chemotherapeutic drug toxicity: doxorubicin.
Drug-induced alopecia (hair loss) is one of the most disturbing side effects of chemotherapy for all patients. In addition, the efficacy of several types of tumor chemotherapy is limited by inflammation of the intestinal lining, oral cavity and esophagus, leading to ulceration and diarrhea and requiring additional medication. Recent animal studies demonstrate that a neutralizing anti-doxorubicin antibody can prevent chemotherapy-induced gastrointestinal toxicity and when applied topically in liposomes, can prevent doxorubicin-induced hair loss (see figure below). The antibody applied topically or taken orally did not compromise the anti-tumor activity of the doxorubicin. Pilot human clinical trials have demonstrated the activity of the topically applied antibodies.
In the United States this year, over 200,000 women diagnosed with breast cancer, as well as approximately 190,000 patients with other cancers, are candidates for treatment with doxorubicin and related anthracycline chemotherapeutic compounds, all of which can be inhibited topically by DoxoRx™. Approximately 25% of these patients will receive doxorubicin, daunorubicin, or idarubicin chemotherapy for three to six months. All of these patients are candidates for DoxoRx™ therapy to prevent hair loss because 95-100% of patients treated with these compounds ultimately lose all of their hair. Currently, there are no effective treatments available to prevent hair loss due to doxorubicin.
The picture below shows four young rats that were treated with doxorubicin. The two on the right were also treated with a topical application of the monoclonal antibody from which DoxoRx™ has been derived8. As you can see, the untreated rats have lost a good deal of hair, while the treated rats have not. PLANET scientists have generated plants producing Protected SIgA™ forms of this antibody. Work on this product has been supported by a Phase I SBIR grant.