The Proprietary Nano-Particle Technology FAQs

The Versamune™ nanotechnology is the first pharmaceutical technology or product to be based on a pure active lipid enantiomer. It is based on the pure active enantiomer of certain biodegradable lipids possessing a positively charged (cationic) head-group. Cationic lipids such as DOTAP (the specific lipid used in PDS0101 and PDS0102) exist as racemic mixtures consisting of the R and S enantiomers.

Enantiomers (or stereo-isomers) are 2 molecules which have identical physical and chemical structure but are mirror images of each other and therefore not super-imposable. A good example of this is our left and right hands. Together they are referred to as racemic mixtures. In certain reported cases, one enantiomer may possess unique biological activity not seen with the other. This is the case with the Versamune™ lipids. The VersamuneTM nanoparticles are made up of the specific pure active enantiomer. By formulating a disease-associated protein or peptide (antigen) with Versamune™, the nanoparticles facilitate uptake of the antigen by the antigen presenting cells of the immune system. The nanoparticles simultaneously modulate the immune system to generate a strong and specific T-cell immune response against the cells in the body infected with or expressing the particular protein or peptide. The result is a potent immune response culminating in eradication of the specific cancerous or diseased cells.

An antigen is any foreign agent, usually a protein or peptide (very small protein), which stimulates the body’s immune system to react in order to eliminate or neutralize the agent.

Unlike typical cancer and infectious disease drugs which are developed to target and kill cancer cells or infectious agents and often have toxic side-effects on normal tissues, Versamune™ primes the body’s own immune system to mount a potent response targeted only at the specific diseased cells (based on the formulated antigen), resulting in eradication of the disease. Versamune™ is therefore being successfully applied to the development of superior preventative and therapeutic/curative vaccines.

In the field of immunotherapies, also called therapeutic vaccines, there are a number of unique characteristics of the VersamuneTM technology and the resulting products.

1. The mechanism by which the immune modulatory or adjuvant effect occurs is unique and minimizes or eliminates all together the toxic inflammation associated with the current adjuvants. The technology is in a unique class of safe and yet potent adjuvants.
2. Tumors are quite difficult to eradicate with vaccines because of the presence of immune suppressive cells which are able to combat the body’s defenses. To block these cells most of the current efforts focus on the use of recombinant antibodies, e.g. Yervoy®. VersamuneTM has been shown to attack and reduce the immune suppressor cell population leading to superior efficacy.
3. Most adjuvants and other immunotherapy technologies are bacteria-derived or based on live virus or bacterial technologies. Other existing nanoparticle vaccines are inert and therefore require the use of other components, such as adjuvants, making them quite complex. The immune-activating effects of the simple lipid-based nanoparticle make the products quite unique in their simplicity and comparatively low in production costs.

The mammalian immune system responds to antigens. For an immune response to occur, the antigen must be taken up by special cells known as antigen presenting cells (APC). Dendritic cells are the most potent antigen presenting cells. The APC must then become activated and present the antigen to the T-lymphocytes of the immune system also known as T-cells.

Two types of T-cells can then be activated and induced to proliferate:

1. Helper T-cells which are involved in activating and directing other immune cells. They are essential in determining antibody activity, and in maximizing the bactericidal activity of other immune cells such as macrophages.
2. Cytolytic T- lymphocytes also called killer T-cells, which attack cells infected with foreign agents, leading to eradication of disease.

   Often the antigen may not be effectively presented to the APC, and/or T-cell proliferation may not occur efficiently, leading to a poor immune response to disease. In the case of cancer, certain classes of cells, known as immune suppressive cells, are also believed to be involved with suppressing a strong immune response against the tumors.

Versamune™ operates by a unique multi-pronged mechanism. The technology is very efficient, not only in facilitating uptake of the vaccine by the antigen presenting cells (APC) of the immune system, but also in activating the immune cells. Versamune™ stimulates the immune system to produce critical substances known as cytokines and chemokines by activating an immune signaling pathway known as the MAP Kinase pathway. These substances are critical to the immune system’s ability to recruit APCs and T-cells (the effector cells of the immune system), and also enhance T-cell proliferation as well as the cytolytic or killing function of the T-cells. The result is efficient eradication of the particular disease associated with the antigen. Versamune™ has been shown to be equally effective with protein or peptide antigens. VersamuneTM has also been shown to inhibit the population of immune suppressive cells in the tumors, therefore making the tumors much more susceptible to attack by the Versamune™-induced T-cells. The exact mechanism by which the latter occurs is not yet fully understood and is still being studied.

No; however, what is unique about PDS’s immune-activating technology is the safe mechanism by which the immune system is activated, therefore avoiding the safety concerns of the current adjuvants. Secondly, the breadth and robustness of the immune modulation resulting not only in CD8+ T-cell induction, but also effective CD4+ helper T-cell induction, antibody induction, and very importantly, reduction of the immune suppressive cell population also make VersamuneTM unique.

A number of traditional adjuvants (immune activators) such as aluminum hydroxide, CpG and Montanide are being evaluated in vaccines and immunotherapies. A number of other bacteria-derived adjuvants are also in clinical trials.

Versamune™ has been evaluated in cancer models. PDS’s lead product, PDS0101, is being developed to treat cancers caused by infection with the human papillomavirus (HPV). Complete regression of the cancer has been demonstrated in preclinical studies. Similar efficacy has been demonstrated in the very aggressive melanoma tumor model with PDS0102.

Superior anti-tumor efficacy has been demonstrated and published with PDS0101 when compared head-to-head with more complex formulations which have demonstrated therapeutic efficacy in on-going clinical trials. The ability to evaluate efficacy and to optimize the formulation in human models further increases the likelihood of success in clinical trials.

The technology is equally effective when used as a preventative prophylactic vaccine. Complete prevention of the cancer was demonstrated in the treated animals.

Significant progress has been made in understanding the immune system and biology of disease. A number of biotechnology companies including ours are applying this knowledge to the development of more effective therapies. Some of the technologies in preclinical and clinical development have been discussed in the preceding questions.

Positively charged lipids as racemic mixtures rather than the pure enantiomers have been used in gene therapy and in the development of DNA vaccines. Although none of these gene therapy drugs have yet to be commercialized, several have successfully gone through human safety clinical trials demonstrating the safety of cationic lipids in humans.

In fact most of the current therapeutic vaccines being evaluated in clinical trials are only administered to terminally ill patients because of the less-than desirable side effects. With the VersamuneTM—based vaccines, it is envisioned that the superior safety profile observed in toxicology studies will be replicated in humans, making these products unique in being able to address and manage several of these diseases at an early stage and providing even greater opportunity for successful treatment outcomes and well as preventative approaches.

The VersamuneTM platform can be applied to a broad range of diseases. In oncology for example, several tumor-associated antigens specific to various types of cancer are suitable for use in the technology. Some examples of such cancers are ovarian cancer, melanoma, colorectal cancer, pancreatic cancer, non-small lung cell carcinoma and breast cancer to name a few.

Antigens derived from infectious pathogens known to cause other cancers may also be included in the formulation of the cationic delivery system. It is estimated that about 20% of the worldwide incidence of cancer can be attributed to infectious pathogens. Some examples of such cancers are cervical cancer, head and neck cancer and anal cancer.

The technology is also being applied to the development of immunotherapies to treat viral diseases. Pathogens which may be targeted include viruses, bacteria etc. Examples of viral pathogens include, Retroviridae (HIV-1), Herpes simplex virus, Picornaviridae (e.g. polio viruses, hepatitis A viruses etc.), and Orthomyxoviridae (e.g. influenza viruses) to name a few.

Finally studies have also been initiated to apply the technology to the development of prophylactic/preventative vaccines. Some of the targets include diseases such as influenza.

Safety. Versamune™ is administered sub-cutaneosuly in low doses. In addition, it does not induce significant production of pro-inflamatory cytokines, further improving safety. The immune responses generated are specific to the diseased cells (due to antigen). The above factors should result in few side effects compared to other competing products. No toxic effects have been demonstrated in any of the toxicology studies performed to date.

Wide Applicability. The Versamune™ technology has broad applicability in the development of novel immunotherapies for the cure of various cancers and infectious diseases. The technology also has utility in the development of vaccines to prevent multiple chronic diseases.

Convenience. All product candidates are intended to be administered via injection on an outpatient basis.

Potency. The Versamune™ technology has demonstrated superior efficacy in published head-to-head studies. This is very likely due to the multiple modes of immune activation.

Production. The simple 2-component formulations are easy and less expensive to manufacture.