DNA-based cytokine immune activators enhance immune responses
Many marketed vaccines today use adjuvants to enhance adaptive immune responses to an antigen (a foreign protein associated with a cancer or infectious disease). Adjuvants can help shape the quality and quantity of immune responses, which is crucial for vaccine immunity and efficacy. Specifically, the addition of an adjuvant such as a cytokine to a therapeutic or preventive vaccine can tailor immune responses more specific to the antigen(s) believed to be important for controlling a targeted cancer or pathogen.
Cytokines are molecules that are involved in nearly every aspect of immunity. They are proteins made by cells in the immune system that contain growth, differentiation, and activation functions that determine the nature, strength, and duration of immune responses and control immune cell movement. The type of cytokine produced in response to an antigen determines whether an immune response is cytotoxic, humoral, cell mediated, or allergic. Among cytokines are chemokines and interleukin (IL) molecules.
Chemokines are a unique type of cytokine that induce chemotaxis, or the movement of white blood cells away from low concentrations of chemokine and toward high concentrations. Specifically, chemokines are designed to direct the chemotaxis of white blood cells to infected tissue during an immune response in order for the immune system to eliminate a cancerous or infected cell or an infecting pathogen.
Interleukins are a type of cytokine that are secreted in response to various stimuli and can elicit a wide variety of responses in cells and tissues, including cell proliferation (increasing the number of cells by cell growth/division), maturation, migration and adhesion as well as cell differentiation (when a less specialized cell develops into a more specialized cell) and activation. These functions are part of what distinguish ILs from chemokines. Overall, ILs can exert both inflammatory and anti-inflammatory actions and can function as both potential preventive and therapeutic targets.
Inovio is developing a portfolio of patent-protected DNA-based cytokine immune activators that, in combination with Inovio’s DNA immunotherapies delivered by electroporation, can increase the potency and efficacy of therapeutic immune responses against cancers and chronic viral infections in humans.
Inovio's portfolio of patent-protected immune boosters (cytokine gene adjuvants) vary in their ability to enhance (activate) therapeutic T cells or preventive antibodies, modulate the type of immune responses produced by the immunotherapy, impact durability of immune responses, and drive immune responses to sites of infection, e.g. mucosal surfaces. Different immune activators can therefore play unique roles in achieving desired immune responses generated by DNA immunotherapies and vaccines.
Moreover, while some protein-based cytokines delivered systemically have been shown to have severe toxicity, likely due to their dosing and systemic delivery, Inovio's DNA-based cytokines and chemokines are delivered together with the immunotherapies as DNA in a plasmid and are produced locally at the injection site to drive the production of immune responses with beneficial, non-toxic systemic effects. Inovio has in its portfolio over ten (10) important cytokine and chemokine genes which have shown in pre-clinical studies the ability to boost either T cell or antibody-based immune responses to the vaccines and therapies.
Inovio has deployed three different DNA immune activators in pre-clinical and clinical studies with electroporation delivery:
- Inovio’s DNA-based IL-12 immune activator enhanced antigen-specific T cell immune responses from its HIV DNA vaccine, PENNVAX®. In that study, 89% of the subjects who received IL-12 DNA together with the PENNVAX® DNA vaccine delivered with electroporation produced a vaccine specific CD4+ or CD8+ T cell response compared to 67% who received the DNA vaccine alone without the IL-12 DNA. Results of this study were published in the peer-reviewed Journal of Infectious Diseases in the article, "Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid IL-12 and impact of intramuscular electroporation for delivery." Inovio plans to test DNA IL-12 in combination with various DNA cancer immunotherapy products in upcoming trials.
- Inovio is currently testing DNA IL-28B in combination with its multi-antigen hepatitis C DNA immunotherapy, INO-8000, in a phase I study in HCV patients. In a pre-clinical study that tested IL-28B in Rhesus macaques, IL-28B was found to significantly influence the function of antigen-specific CD8+ T cells. Rhesus macaques immunized with Inovio’s DNA-based IL-28 immune activator had CD8+ T cells that exhibited increased cytotoxic activity, which included perforin release and a significant ability to kill target cells in an antigen specific manner. This suggests that Inovio’s DNA based IL-28B immune activator has a potent impact on the immune system.
- In pre-clinical studies, Inovio’s DNA-based IL-33 immune activator, in combination with a DNA immunotherapy targeting HPV-16, led to rapid and complete tumor regression in mice. The adjuvant/immunotherapy combination induced potent CD4+ and CD8+ T cells. Notably, inclusion of the DNA-based IL-33 immune activator significantly increased the magnitude of vaccine-specific CD8+ T cell responses. The peak vaccine-induced expansion of CD8 T cells at 14 days after vaccination correlated with complete tumor regression. Results of this study were published in Cancer Research in a paper titled: "Alarmin IL-33 acts as potent immunoadjuvant enhancing antigen-specific cell-mediated immunity and inducing potent anti-tumor immunity."
Inovio will continue to expand its R&D and clinical testing of its portfolio of immune activators to further characterize their capabilities and optimize immune responses generated by its various DNA vaccine and immunotherapy products.
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