Immune Stimulation Through a First-in-Class TLR Tri-Agonist
Our core technology is based on a plant virus, cowpea mosaic virus, (CPMV). This naturally occurring virus is not infectious in humans or animals, yet upon intratumoral administration is perceived by cells of the immune system as foreign, inducing potent and broad immune responses which then recognize and fight tumors. The same technology can be quickly adapted for use as an adjuvant and epitope display platform for prophylactic and therapeutic vaccines against cancers and infectious diseases.
Technology is based on innate immune system activation
Pathogen Associated Molecular Patterns (PAMPs)
on exterior of CPMV nanoparticle capsid
Recognized by TLRs 2 and 4
Increased IL-12, MIP1, CXCL10, IFNγ
Stimulation of immune response
Recruitment of inflammatory cells
Synergistic TLR activation of MIE-101
Our preclinical studies have demonstrated that the activation of multiple TLRs by a single agent provides increased immune stimulation versus targeting individual TLRs. Results of MIE-101 targeting TLRs 2,4 &7 together versus individually include:
More recruited and activated dendritic cells
Stronger inhibition of T-regulatory cells
Bridging of innate and adaptive immunity
Increased T-effector cells
Broad and consistent anti-tumor effects
Broad and consistent antitumor immune responses
CPMV is not an oncolytic virus, meaning it does not target or destroy tumor cells directly. Rather, as a foreign entity, CPMV engages evolutionary conserved pattern recognition receptors, (PRRs), on and inside host immune cells, activating the cells specifically through a family of receptors discovered in the 1980's, named toll-like receptors (TLRs). These receptors function as a first line of defense against foreign microbes, activating immune cells to destroy the microbe and to stay on guard against future recurrence. Most TLR activating treatment candidates in development for oncology indications target a single TLR. CPMV engages multiple TLRs which has been shown to increase the breadth and potency of the immune response. TLRs are conserved across mammalian species, which provide rationale for preclinical data that demonstrate consistent anti-tumor results when CPMV is used to treat multiple tumor types, whether in established preclinical animal models or in naturally occurring cancers in canine companion animals. Supporting the consistency of TLRs across species, our researchers have observed similar signs of immune activation when CPMV is assessed with human immune cells in vitro.
Our lead immuno-oncology candidate, MIE-101, is derived from natural CPMV. MIE-101 has repeatedly demonstrated single agent anti tumor activity, as well as therapeutic synergy when combined with immune checkpoint inhibitors and other standard of care treatments in several preclinical tumor models.
MIE-101 is administered directly into tumors to activate neutrophils and other innate immune cells present in the tumor environment. Multi-TLR activation induces immune cells to recognize and fight the tumor. These first-responder innate immune cells also secrete chemicals responsible for the attraction and training of additional immune cells to recognize tumor antigens and reinforce the anti-tumor activity. Data show that this cycle leads to a broader adaptive immune response capable of fighting not just the primary tumor treated, but also distant sites of tumor growth. Our preclinical studies have also demonstrated a durable immune memory response that provides protection from future recurrence or re-challenge of the cancer.
ssRNA from interior of CPMV nanoparticle
Recognized by TLR 7
Induces type-I IFN and other inflammatory cytokines
Drives NK cell, dendritic cell and T cell activation