Versamune® Platform

The Versamune® Platform Activates all Critical Mechanisms of Cancer Immunotherapy

ACTIVATING AND DIRECTING THE IMMUNE SYSTEM TO UNLEASH A POWERFUL AND TARGETED ATTACK AGAINST CANCER CELLS

PDS Biotechnology’s Versamune® platform is based on novel and proprietary synthetic cationic lipids. Versamune® facilitates efficient uptake, processing and presentation of disease-related antigens, such as tumor antigens, via the MHC Class I pathway to killer T-cells in order to prime the Killer T-cells to recognize the cancer. Versamune® simultaneously induces a powerful stimulation of type I interferons and associated chemokines resulting in a powerful and targeted immune response against the cancer cells. Versamune® also suppresses the tumors defenses, therefore, making the cancer more susceptible to T-Cell attack.

CATIONIC LIPIDS – NOVEL APPROACH TO EFFECTIVE IMMUNOTHERAPY

PDS has identified certain proprietary positively charged lipids (cationic lipids) that have the ability to spontaneously form nano-particulate structures. This facilitates their efficient uptake by the immune cells of the body, and also their ability to destabilize cell endosomes (see section on Accessing the MHC Class I Pathway below). These cationic lipids, based upon their structural characteristics also have the ability to act as potent immune activators (see section on Activation of Type I Interferon Genes below). These characteristics of cationic lipids have been exploited to overcome critical limitations of immunotherapy to develop superior immuno-oncology products which are being tested in multiple human clinical trials.

VERSAMUNE® PLATFORM ACTIVATES THREE CRITICAL MECHANISMS OF CANCER IMMUNOTHERAPY

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Accessing Class I & II Pathways

Antigen uptake & priming of killer T-cells

Type I Interferon Activation

Stimulation of CD8+ T-cell response

Inhibition of Tregs and MDSC

Overcoming tumor immune suppression

Versamune® was designed, and has been proven, to facilitate antigen uptake, processing, and entry into the cytoplasm. This enables critical access of antigens to the MHC Class I pathway in order to effectively prime targeted killer T-cell responses.

Versamune® activates a powerful and targeted T-cell response via stimulation of type I interferon (IFN) genes. Lymph node studies have demonstrated strong stimulation of type I interferons such as IFNα1 and IFNβ1, as well as downstream chemokines such as CCL2 and CxCL10. The localized immune response contributes toward high activation & proliferation of killer (CD8+) T-cells without any of the typical side effects usually associated with cancer immunotherapy.

In preclinical studies, subcutaneous administration of Versamune® was associated with significant reduction in both the regulatory T-cell (Treg) and myeloid derived suppressor cell (MDSC) populations.

This effect is believed to be a major contributor to Versamune®’s observed ability in preclinical studies to overcome a tumor’s ability to evade T-cell attack and inhibit tumor growth or eradicate tumors in several aggressive tumor models.

ACCESSING THE MHC CLASS I PATHWAY

The figure below (quadrants A & B) demonstrates the unique ability of PDS’ cationic lipids to facilitate antigen uptake, processing and effective endosomal accumulation in immune cells.

In quadrant A, when an immune cell is treated with the DQ-OVA fluorescent model antigen combined with Versamune® nanoparticles, a strong green fluorescence is observed. This confirms that Versamune® has facilitated the cellular uptake and processing (breakdown) of the DQ-OVA. This processing of antigens is extremely important, because CD8+ T-cells can only be primed by being presented with correct 8-11 amino acid sequences (epitopes).

Quadrant B shows the resulting red fluorescence. This confirms that the processed antigen has successfully entered into the endosomes. Cationic lipids have been conclusively demonstrated to destabilize endosomal membranes (FEBS Lett 1997; 414: 187-192, Biochim Biophys Acta 1994; 1189: 195-203). This “opens up the door” and allows a critical step to occur – entry of processed antigens into the cytoplasm of dendritic cells, where it can then access the MHC class I presentation pathway to present antigen to CD8+ T-cells and hence prime CD8+ T-cells.

Quadrants C & D show the results of dosing an immune cell with a combination of the DQ-OVA and a competing “strong T-cell adjuvant”. No antigen uptake or processing is observed. These studies highlight the key difficulty for immunotherapy in generating in-vivo antigen-specific CD8+ T-cell responses, and why the Versamune® synthetic lipid technology is unique in its ability to overcome this obstacle to facilitate superior levels of CD8+ T-cell induction.

ACTIVATION OF TYPE I INTERFERON GENES

Stimulator of Interferon Genes (STING) has been identified as a primary mediator of innate immunity, and induces the expression of type I interferons, cytokines, and T-cell recruiting chemokines that result in the activation of antigen presenting cells, effector cells such as natural killer (NK) cells, and disease-targeting T-cells.

PDS has recently identified the ability of certain positively charged (cationic lipids), depending on their structure, to act as potent stimulators of type I interferon (IFN) genes. PDS’ research and development programs have also led to the first identification and reports on the effects of the cationic lipid enantiomeric specificity on the ability to effect potent and targeted immune activation.

PDS, using nano-string technology and other immunological methods, has conclusively demonstrated that its Versamune® platform acts as a potent activator of type I interferon genes, as well as related chemokines such as Cxcl10 and CCL2.   Induction of these chemokines leads to prolonged influx of high levels of T-cell infiltration into lymph nodes and effective activation and proliferation of T-cells.

By taking advantage of these two unique characteristics of the Versamune® platform and administering the lipids in combination with tumor antigens, high levels of tumor specific “high quality” poly-functional CD8+ killer T-cells are generated. These poly-functional T-cells are well documented to be much more effective in their cell killing function than mono-functional or single cytokine-inducing T-cells.

As shown in the flow diagram below, a cascade of localized immunological events is initiated at the site of injection. Immune cells loaded with antigens and lipid migrate into the lymph nodes. Activation of type I interferons in the lymph nodes enables efficient priming of large quantities of CD4+ and CD8+ antigen-specific T-cells. These effectively primed T-cells then migrate in large numbers into the tumor micro-environment, where they induce the killing of tumor cells.

OVERCOMING TUMOR IMMUNE SUPPRESSION

The Versamune induced T-cell response results in a reduction of the number of immune suppressive regulatory T-cells (Tregs) and therefore “de-camouflages” the tumors, making them more susceptible to T-cell attacks. The presence of T-regs is known to increase in number in tumor cells and thus plays a role in activating tumor targeting T-Cells.

The Versamune® approach is effective in altering the biology of the tumor’s microenvironment by shifting the balance in the ratio of killer T-cells to Tregs significantly in favor of the CD8+ T-cells, ultimately leading to effective lysis or killing of infected/cancer cells.

Versaume Flow diagram (image)

SUCCESSFUL INDUCTION OF STRONG CD8+ T-CELL RESPONSES IN HUMANS

Versamune®’s unique ability to prime high levels of antigen-specific CD8+ killer T-cell responses has been confirmed in a Phase 1/2a human clinical trial. Versamune®’s excellent safety profile, first observed in animal toxicology studies, was also corroborated with no clinically relevant toxicities observed at any dose in humans.

The combination of Versamune®’s human CD8+ T-cell induction efficacy and excellent safety profile is an important step toward the development of next-generation therapies to treat both early- and late-stage cancers. The mechanism of action also suggests that Versamune®-based products will be uniquely suited for use in combination with other immuno-oncology platforms to develop powerful cancer therapies. Powerful enhancement of anti-tumor efficacy, with a 3-fold increase in complete tumor regression when the Versamune®-based immunotherapy is combined with a checkpoint inhibitor has already been demonstrated in a stringent preclinical colon cancer tumor study.

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    PDS Biotechnology is a clinical stage biopharmaceutical company developing novel cancer immunotherapies and vaccines for infectious diseases.

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    PDS Biotechnology Corporation
    Commercialization Center for Innovative Technologies (CCIT)

    675 US Highway One
    North Brunswick, NJ 08902

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