Current Collaborative Projects

(1) Targeting of Human Immunodeficiency Virus (HIV) Reservoir Cells

Background: As of 2003, it is estimated that approximately 42 million people are infected worldwide with HIV. Since then this number has continued to grow. It is known that HIV resides in long-term and long-lived reservoir cells in "sanctuary" endosomal compartments inaccessible to normal immune system recognition and attack. As a result, HIV cannot be cleared from the immune system, leading to a state of chronic infection. State-of-the-art pharmacologic treatments do not eradicate these viral reservoirs which remain hidden for weeks to years within the intracellular compartments.

Even if current pharmacologic treatments, directed at virus in it’s actively replicating state, were capable of reaching these compartments, the intact, dormant,non-replicating virions stored therein would not be affected.

As a result, cells harboring the HIV reservoir, comprising several types of key immune cells, are invulnerable to any known treatments currently available.

Principle: By employing our patented carbohydrate- coated nanospheres, we have addressed HIV's "Achilles Heel", namely its immutable molecular requirement for entering and infecting cells of the immune system. We have obtained proof of concept for specific targeting of HIV reservoir cells with site-specific compound delivery into the intracellular compartments (endosomes) exploited by the virus as sanctuary “storage” compartments.

Additionally, by effectively delivering a non-toxic HIV-specific plant lectin, all endosomal stored virions are agglutinated, thereby killing the stored viruses and creating large protein complexes that may be successfully degraded, either by the infected cell's own digestive enzymes (which is what nature ordinarily does with most other infectious agents) or by enzymes which may be co-delivered with the lectin.

Perspective: By closing one of the immune system's "security holes", our technology offers hope for eradicating HIV from patients for whom current treatments may offer, at best, only a state of chronic stability, requiring that treatments are never discontinued and/or risking that viral strains never grow resistant to treatment.

Reference: Steinbrook R. The AIDS Epidemic in 2004: N Engl J Med 2004; 351:115-7.

(2) Targeting of Hepatitis C Virus (HCV) Reservoir Cells

Background:It is estimated that 170 million people in both the industrial and developing world are infected with HCV, which in most instances leads to a chronic viral infection with devastating short and long term disabilities, cirrhosis, hepatocellular carcinoma, and death. While mostly different types of immune cells in the liver and extra hepatic sites of infection cells are infected from those cells infected with HIV, and the anatomical and histological locations differ, the mechanism leading to HCV viral chronicity and reservoir storage are identical.

Principal: Although target cells differ from those in HIV infection, these cells express molecular targeting structures that are addressed successfully with our technology.

Perspective: Identical to that described above for HIV infection.

Reference: Szabo E, Lotz G, Paska C, Kiss A, Schaff Z. Viral Hepatitis; new data on hepatitis C infection: Pathol Oncol Res 2003; 9:215-21.

(3) Novel Active HCV Vaccination

Background: With 170 million people infected worldwide (see Reference 3), HCV is the most common viral infection known. While global vaccination appears imperative because of the serious sequellae (liver cirrhosis, acute-on-chronic liver failure, liver cancer, etc.), there is no HCV vaccine at hand.

Eukaryotic cells recognize bacterial CpG Oligonucleotides, via their toll-like receptors (TLRs), as being different from their own genetic information. In humans, TLRs are expressed in certain immune cells and, in some of these, are expressed only intracellularly. TLR engagement by CpG oligos sets a nonspecific danger signal which, when combined with a specific pathogen signal, enhances an individual's response to the specific challenge (see References 1,2).

Principle: Rodos BioTarget, on behalf of LTBH, has a signed LOI and is planning a confidential study that will utilize our technology to address plasmacytoid Dendritic cell (pcDCs) for actively vaccinating against a variety of infectious diseases, and most prominently, Hepatitis C, by targeting TLR-9 toll-like receptors. We believe this may permit considerable enhancement of pcDC-dependent vaccination strategies against HCV.

Perspective: To significantly increase global protection against HCV infection.

References:

1. Uhlmann E, Vollmer J. Recent advances in the development of immunostimulatory Oligonucleotides: Curr Opin Drug Discov Devel 2003; 6:204-17;

2. Vollmer J, Jepsen JS, Uhlmann E, Schetter C, Jurk M, Wader T, Wullner M, Krieg AM. Modulation of CpG oligodeoxynucleotidemediated immune stimulation by locked nucleic acid (LNA): Oligonucleotides 2004;14:23-31

3. SzaboE, Lotz G, Paska C, Kiss A, Schaff Z. Viral hepatitis: new data on hepatitis C infection. Pathol Oncol Res 2003; 9:215-21.

(4) Novel Active Vaccination against Malignant Diseases (Lymphoma)

Background: It is estimated that there are 61,000 new lymphoma cases annually in the USA alone (see Reference 2), which projects to approximately 200,000 new cases annualy in the industrialized nations (300M people vs. 1B people).

See Number (3) above for similar technical background.

Principle: Identical to Number (3) above. In this situation, plasmacytoid DCs will be addressed with institutional collaborators for active cancer vaccination, with special emphasis on lymphoma. (Reference 1).

Perspective: To significantly increase the success of lymphoma treatment.

References:

1. Krieg AM. Antitumor applications of stimulating toll-like receptor 9 with CpG Oligodeoxynucleotides. Curr Oncol Rep 2004: 6:88-95.

2. American Cancer Society. Cancer Facts & Figures 2003: Available online from

http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf

(5) Autoimmunity: Novel Treatment for Autoimmune Eye Diseases

Background: Thyroid-associated Ophthalmopathy (TAO) is an autoimmune condition frequently associated with Graves' disease, an autoimmune disorder of the thyroid. We recently participated in a collaborative study identifying a previously unacknowledged population of immune cells in the retro orbital space that is likely responsible for most symptoms and exacerbations of this eye disease (see Reference 1). While only a limited population is affected by TAO, additional work in this area will have impact upon other autoimmune disorders, and thus we have decided to pursue continued collaborations.

Principle: Targeting of inflammatory gamma -T cells with our technology by injection into the eye or topical application of a liposome-permeating ointment.

Perspective: To significantly improve the outcome of TAO treatment, and to prevent disfiguring or debilitating retro orbital surgery in patients seriously affected by this disease.

References: 1. Eckstein AK, Quadbeck B, Tews S, Mann K, Kruger C, Mohr CH, Steuhl KP, Esser J., Gieseler RK. Thyroid associated Ophthalmopathy: evidence for CD4+ gamma T Cells; de novo differentiation of RFD7+ macrophages, but not RFD1+ dendritic cells; and loss of gamma and alpha beta T cell receptor expression. Br J Ophthalmol 2004; 88:803-8.

2. E-medicine: Thyroid Ophthalmopathy: Available online from htttp://www.emedicine.com/radio/topic485.htm

3. Quadbeck B, Stucke M, Eckstein AK, Heise DJ, Mann K, Gieseler RK. Dysregulation of TNF/TNFR super family members: a systemic link between intra- and extra thyroidal manifestations in Graves' disease: Scand J Immunol 2006;64:523-30.