NVI-9010 Targeted Cancer Therapeutic Optimized to Treat Metastatic Cancers
NanoVector is a pre-clinical stage biopharmaceutical company commercializing a unique nanoparticle drug delivery system developed by two Professors at North Carolina State University (NCSU). Using a patented plant virus nanoparticle (PVN) drug delivery system NanoVector has developed a targeted therapeutic optimized to treat metastatic tumors. This nanoparticle formulation, NVI-9010, consists of a PVN with a cargo of the approved, versatile anticancer drug: doxorubicin hydrochloride (Dox) at ~700 molecules per PVN virion) and an array (up to 180) of proprietary N-cadherin targeting peptides on the PVN surface. NVI-9010 is currently undergoing initial pre-clinical studies for melanoma and ovarian cancers under a $1.2M NCI Phase 2 SBIR contract.
The PVN has significant potential advantages over antibody-drug conjugates (ADCs) and free drugs as follows:
1) Achieves greater drug payload delivery at the targeted cell receptor entry point – The PVN has a hollow internal cargo chamber 17 nm in diameter. Loading of >700 molecules of Dox is typically achieved. Each PVN carries this payload into the cell. In contrast, an ADC would nominally contain only one drug molecule. Unlike PVNs and ADCs, free drug molecules do not specifically target cell surface receptors.
2) Uses cytoplasm in the targeted cell as an auto-trigger. A PVN that enters the targeted cell is automatically triggered by low calcium and magnesium in the cytoplasm, resulting in the eventual opening of PVN pores and subsequent release of the drug payload automatically. The drug portion of the ADC is normally not “triggered” to be released.
3) Provides a delayed release of the encapsulated drug. Once triggered to open, the PVN does not open for many hours, so it has time to travel to locations deep within the cell before drug release. It is less certain when the drug payload of the ADC would be released and may be a function of the specific chemistry involved. Free drug is effectively in a “released” form as soon as it crosses the cell membrane and enters the cytoplasm, a location from which it is easily pumped out by multidrug resistant cancer cells.
4) Protects the drug cargo and achieves a high safety profile. The PVN encapsulates and protects its drug cargo, sealing it off from blood, tissue fluid, and cytoplasm until release in the cytoplasm. The ADC has the drug molecule exposed, so the drug is not protected. Certain drugs, may be highly reactive and should be protected.
5) Enables targeting of N-cadherin expressed on cancer cells, and does not target N-cadherin on normal cells. As discussed in more detail earlier, the PVN, will target N-cadherin on tumor cells that express it, probably as far as the PVN can reach into the loose tumor mass, especially in tumors with cells that loosen up to become migratory (prior to and during metastasis). The PVN is not expected to be able to target the N-Cadherin any in healthy cells, since the PVN cannot fit into the normal cell junctions (a space of 30 nm or less) where N-cadherin is situated. On the other hand, an ADC or a free drug could more readily diffuse into cell junctions, e.g. in the nervous system.
6) Targets and destroy circulating tumor cells (CTCs) e.g. via N-cadherin targeting. Circulating tumor cells are migratory, and dosing of PVN in the circulatory system would provide an enormous ratio of PVNs to CTCs, providing ample opportunity to target and destroy these migratory cancer cells that are believed to be responsible for new tumor sites.
We believe that if multidrug resistance and metastasis could be effectively dealt with, cancer would become a chronic disease like diabetes, in the worst case, and in the best case go into complete remission. A nanoparticle technology capable of delivering to a cancer cell a sufficient number of anticancer drug molecules deep within the cytoplasm could overcome multidrug resistance, a cancer defense localized in the cell membrane efflux pumps. If distinctive cell surface molecules associated with metastasis could be selectively targeted, then metastasis might also be overcome. Therefore, the PVN with active targeting of N-cadherin, which is expressed by many tumor types and many cancers and is associated with metastatic disease, is a potentially powerful and transformative delivery system. In addition, based on initial animal studies, the PVN confers a high safety profile on the drugs delivered.
Biologic Nanoparticle Drug Delivery System. NanoVector’s differentiated technology is based on what is perhaps the world’s first commercially viable biologic nanoparticle: a plant virus nanoparticle. This plant virus enables a low-cost drug delivery system that is stable in blood and has a delayed release triggered by cytoplasmic entry as discussed below. This plant virus, Red Clover Necrotic Mosaic Virus (RCNMV), is harmless to humans, and is found in our food chain. It is one of the most robust viruses known and can live in the soil for months. It is an RNA virus with no DNA. RCNMV is found in fruits, such as cherries, and in drinking water reservoirs in temperate climates. It is often consumed by humans and is readily broken down and excreted in the urine (unpublished data). RCNMV, like other plant viruses that have been used as vaccine vectors, is of low immunogenicity and when delivered intravenously can enter a targeted cancer cell via endocytosis. It is small enough (36 nm) to readily penetrate into solid tumors.
NanoVector’s biologic nanoparticle is in effect a “smart bomb”! When the therapeutic agent-carrying nanoparticle enters a cell it senses a change in chemical environment and automatically unloads its cargo. Therefore the highly toxic therapeutic agent is released only in a cell, never in the blood stream as with chemically synthesized particles that depend upon capsule degradation or require an external trigger, such as an electromagnetic field, to open the nanoparticles for the release of their content. The benefit derived from this feature is the minimization of the horrendous side effects of highly toxic free drugs in the blood stream.
Other important features of the PVN are listed below. In summary the PVN is based on a harmless plant virus that is in the human food chain and that has evolved for millions of years to have all the key features required for a successful drug delivery system that to date has not been duplicated by the best chemists. The key end user values are affordable therapy, improved prognosis and improved quality of life.
N-Cadherin cell surface receptor targeting. The biggest challenge in targeting cancer cells with a nanoparticle drug delivery system is identifying a cell surface receptor that is found on cancer cells but not targetable on healthy cells. NanoVector has successfully addressed this challenge by targeting the N-Cadherin cell surface receptor. In healthy cells N-cadherin is found in cell-to-cell junctions in the nervous system, opening the door for severe side effects if small molecule drugs or antibody-drug conjugates are used to target this molecular receptor. However the NanoVector nanoparticle is too large to enter the cell junctions of healthy cells. NanoVector has demonstrated that its plant virus nanoparticle (PVN) can effectively target N-cadherin on cancer cells but not in cell junctions between normal cells.
In cancer cells, N-cadherin expression on the cell surfaces is almost universal once the cancer has metastasized. N-cadherin expression occurs on many tumor types, on many different cancers, especially when the tumor cells are getting ready to break away from the initial tumor and become migratory and invasive during metastasis. When the malignant process known as Endothelial-Mesenchymal Transition (EMT) occurs, N-cadherin is typically expressed, since an E-cadherin to N-cadherin switch occurs on cell surfaces with the transition from the more rigid primary tumor cells to less rigid or more amoeba-like cells: a hallmark of metastatic disease. EMT, with corresponding N-cadherin expression on cancer cells, is associated with increases in cell motility and invasiveness in many cancers. It is therefore important to target this cell population. The expression of N-cadherin in early breast tumors is very low, but this expression rises substantially as metastases occurs and is almost universal in metastases. Some cancers express N-cadherin in early stages, for example: malignant melanoma – an inherently metastatic disease where N-cadherin expression appears to be ubiquitous. Very close spacing between adjacent cells occurs with N-cadherin that is normally found on cell surfaces in the nervous system, since N-cadherin is an adhesion molecule on normal cells. Whereas small molecules used for therapeutic purposes could diffuse into the space between N-cadherin-mediated cell junctions, presumably 30 nanometers or less in width (7), the NanoVector plant virus nanoparticles with N-cadherin targeting selectivity are too large to diffuse into this space and are believed to be transported primarily via convection in the circulatory system and not by diffusion. However, nanoparticles with N-cadherin selectivity could attach to N-cadherin on cancer cells, where the N-cadherin is exposed, especially in the case of EMT, where cells begin to loosen up from the main tumor and in metastasis.