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Mosaic Technology Overview

Our lead veterinary in situ vaccine treatment candidate, MIE-201, is derived from a plant virus known as cowpea mosaic virus, (CPMV). This plant viral nanoparticle is not infectious in mammals, but is recognized as a danger signal by the immune system.  Direct injection of CPMV into tumors has demonstrated a robust local immune response inside the tumor, recruiting immune cells that respond to and are activated by the plant virus and ultimately target the tumor itself.  Anti-tumor immune responses within the treated tumor have been shown to initiate immune surveillance resulting in durable, systemic antitumor immunity and destruction of distant untreated tumors.

Studies assessing MIE-201 in canine companion animals consistently demonstrate antitumor activity and a positive safety profile utilizing the nanoparticle as a single agent or in combination with standard therapies against naturally occurring cancers. Data to date show similar effects as those observed in preclinical tumor models evaluating CPMV. This consistent antitumor activity and immune activation measured in preclinical studies and in the treatment of naturally occurring cancers in dogs may be due to the way MIE-201 is recognized by cells of the immune system. Immune cells in all mammals share similar receptors that have evolved to sense foreign entities. This process activates the cells to recognize and fight invaders. MIE-201 has been shown to engage multiple receptors leading to potent immune stimulation and antitumor effects in dogs with spontaneous solid tumors.  New studies are planned to further assess MIE-201 in several canine cancers.

 

The science supporting MIE-201 was the result of over twenty million dollars in research funding and has been widely published in leading peer-reviewed scientific journals.

MIE-201: Lead Canine 

in situ Vaccine Candidate

Key Highlights
  • Intratumoral immunotherapy

  • Not an oncolytic virus

  • Based on a non-infectious plant virus (cowpea mosaic virus, CPMV) nanotechnology platform 

  • Recognized by Pattern Recognition Receptors (PRRs) that activate the innate immune system

  • Robust anti-tumor responses in preclinical studies across multiple tumor types

  • Activates innate immune cells including neutrophils and NK cells (tumor killing function, cytokine secretion) and cytotoxic and memory T cells (adaptive immune response)

  • Downregulates MDSCs and expands tumor-specific T-cells (as indicated by upregulation of MHC II and CD86) – and therefore is distinct from checkpoint inhibitors that are not tumor-specific

  • Not neutralized by anti-drug antibodies (ADA)

  • Single agent and combination therapy synergy in multiple preclinical tumor studies

  • Single agent and combination therapy activity in dogs with naturally occurring tumors

  • Human immune cell activation is consistent with immune activation in preclinical animal models

  • Preclinical study results and studies in dogs with naturally occurring tumors support combination potential with current standard of care including checkpoint treatments, chemotherapy and radiation

  • Immune memory and protection from tumor rechallenge in preclinical studies

Activating the Immune System Through Multiple Signaling Pathways

Combination of immune activation and blocking tumor-based immune inhibition

MIE-201 Immune

stimulation effects

Immune activation through multiple Pattern Recognition Receptors (PRRs)

  • Neutrophil activation (tumor killing function, cytokine secretion) and cytotoxic and memory T cells (adaptive) ​

  • Downregulates MDSCs and expands tumor-specific T cells (as indicated by upregulation of MHC II and CD86) ​

  • Not cytolytic – and therefore distinct from oncolytic vectors

  • Distinct from checkpoint inhibitors

Mechanistic Details

Wang, Fiering and Steinmetz: Cowpea Mosaic Virus Promotes Anti-Tumor Activity and Immune Memory in a Mouse Ovarian Tumor Model. Advanced Therapeutics. 2019, 2, 1900003

Intratumoral MIE-201 activates multiple innate immune responses and antitumor T cell responses. MIE-201 nanoparticles are recognized and taken up by innate immune cells including neutrophils. The subsequent early inflammation phase (upregulation of IL-12, IL-6 and IFN-γ) recruits, activates, and polarizes immune cells, e.g. switch from pro-tumor to anti-tumor macrophages (M2 to M1 switch). Reduced levels of IL-10 and TGF-β further promote infiltration by N1 and M1 anti-tumor neutrophils and macrophages amongst other immune cells. The populations of DCs, NK cells, and myeloid cells positive for MHC II/costimulatory molecules are increased by the pro-inflammatory tumor microenvironment. Naive tumor infiltrated T cells can then engage with MHC on those potent APCs presenting tumor antigens. These tumor-specific T cells can activate tumor cell cytotoxicity and further expand to effector memory T cells.

MIE-201 is Recognized by Innate Immune Cells, Inducing Antitumor Immunity

  • Activates innate immune system through multiple pattern recognition receptors (PRRs)

  • Activates and recruits innate immune cells through key cytokines (IFNy, type I IFN)

  • Innate immune cells (M1 macrophages, neutrophils, NK cells) kill tumor cells releasing tumor-associated antigens / neo-antigens

  • Innate immune cells become APCs; link to adaptive immunity

  • Potent and durable anti-tumor immunity mediated by CD8+ T cells and memory cells

Mao C, Beiss V, Fields J, Steinmetz NF, Fiering S. 2021, Cowpea mosaic virus stimulates antitumor immunity through recognition by multiple MYD88-dependent toll-like receptors. Biomaterials. 2021 May 25;275:120914

Innate Immune Cells are Constantly Looking for Viral Threats

  • Pattern Recognition Receptors (PRRs) on innate immune cells identify viruses through their pathogen-associated molecular patterns (PAMPs)​

  • Once a virus is recognized, a robust immune response occurs to eliminate the disease​

  • In the tumor microenvironment, a robust immune response can result in tumor recognition and an anti-tumor immune response

Turning Cold Tumors Hot for Antitumor Responses
MIE-201
Intratumoral Administration

MIE-201 is a naturally occurring plant virus that does not replicate in mammals but contains features of foreign pathogens

Tumor Microenvironment

Innate immune cells in tumors, constantly on guard for viral pathogens,  quickly recognize MIE-201 and become activated to fight