Developing Novel Drugs for Treatment and Diagnosis of Cancer

Technology & IP

LIGHT, HOT and GLOW2 are optimized PLEs that interact with lipid rafts, which are specialized microdomains within cell membranes. Importantly, the core chemical structure shared across all three products provides selective targeting of cancer cells, including cancer stem cells, in preference to normal cells (due to enrichment of lipid rafts in the former). The cancer-targeting PLE carrier molecule was deliberately designed to be coupled to imaging or therapeutic molecules. For example, iodine can be attached via a very stable covalent bond resulting in two distinct products differing only with respect to the isotope of iodine they contain – HOT contains short-lived radioactive I-131 and LIGHT contains the even more short-lived radioactive I-124. Because of their chemical identity, LIGHT also represents an ideal biomarker that can be used to predict tumor sensitivity to HOT and, potentially, establish an efficacious dose in individual patients. Other, non-radioactive molecules can also be attached to the PLE core. In the case of GLOW2, this is an infrared emitting fluorophore (800 nm) whose signal can penetrate up to approximately 1 cm of tissue. This may enable GLOW2’s use to visualize tumor margins during cancer surgery (effectively acting as an adjunct therapeutic agent) and to non-invasively detect relatively superficial tumors. Thus, to date, three cancer-targeted product profiles have been generated from a single chemical core structure that is the foundation of our technology platform – a diagnostic PET imaging agent, LIGHT, a molecular radiotherapeutic agent, HOT and a non-radioactive optical imaging agent to increase the success of cancer surgery and non-invasively image certain tumors, GLOW2.

Using another fluorescent-labeled PLE (CLR1501 or GLOW1), selective uptake and retention has been demonstrated in cancer cells in vitro. Twenty-four hours after treatment, a variety of human tumor cell types (melanoma, colorectal, uterine, pancreatic, ovarian, glioblastoma) show six- to ten-fold more staining with GLOW1 relative to normal cells (e.g., skin fibroblasts). Significantly, uptake/retention was also seen in cancer stem cells, which are known to be relatively resistant to both chemotherapy and radiation and may therefore contribute to eventual relapse of disease following conventional chemotherapy.

Malignant tumor targeting, including targeting of cancer stem cells, has also been demonstrated in vivo. For example, mice without intact immune systems, and inoculated with Panc-1 (pancreatic carcinoma), were injected with GLOW2 24 or 96 hours prior to imaging. In vivo optical imaging showed pronounced accumulation of GLOW2 in tumors versus non-target organs and tissues. Similarly, PET imaging of tumor-bearing animals administered the imaging agent LIGHT clearly showed selective uptake and retention by both primary tumors and metastases in 52 of 54 models including colon, glioma, triple negative breast and pancreatic tumor xenograft models. Furthermore, PET/CT analysis following co-injection of HOT (for therapy) and LIGHT (for imaging) revealed time-dependent tumor shrinkage and disappearance (over 9 days) in a cancer xenograft model. Finally, we believe that the capability of our technology to target cancer stem cells in vivo was demonstrated by treating tumor-bearing mice with GLOW1 and then removing the tumor and isolating cancer stem cells, which continued to display GLOW1 labeling even after three weeks in cell culture.

The basis for selective tumor targeting of our compounds lies in differences between the plasma membranes of cancer cells as compared to those of most normal cells. Specifically, cancer cell membranes are highly enriched in “lipid rafts”. Lipid rafts are specialized regions of the membrane phospholipid bilayer that contain high concentrations of cholesterol and sphingolipids and serve to organize cell surface and intracellular signaling molecules (e.g., growth factor and cytokine receptors, the phophatidylinosotol 3-kinase (P13K)/Akt survival pathway). Data suggests that lipid rafts serve portals of entry for PLEs such as LIGHT, HOT and GLOW2. The marked selectivity of our compounds for cancer cells versus non-cancer cells is due to the facts that phospholipid analogs such as PLEs have high affinity for cholesterol and that cancer cells have far more cholesterol-rich lipid rafts. In addition to accumulating in lipid rafts, LIGHT, HOT and GLOW2 are transported into the cytoplasm, where they distribute to organelle membranes (mitochondria, ER, lysosomes) but not the nucleus. The pivotal role played by lipid rafts is underscored by the fact that disruption of lipid raft architecture suppresses uptake of PLEs into cancer cells.

Intellectual Property

We have established a broad U.S. and international intellectual property rights portfolio around our proprietary cancer-targeting phospholipid ether technology platform including LIGHT, HOT and GLOW2.

Our proprietary rights include patents and patent applications that are either owned by us or exclusively licensed to us by the University of Michigan (the Michigan patents). LIGHT and HOT are covered by the Michigan patents that provide compound (composition of matter) coverage in the US and Canada and expire in 2016. Our patents and applications cover methods of use, composition and method of manufacture related to LIGHT, HOT, GLOW2 and other PLEs. Many of these patents and applications are filed in key commercial markets worldwide. These patents will generally expire between 2025 and 2030 unless extended.

In particular, LIGHT is covered by the Michigan compound patents as well as two of our U.S. patents, one of which is directed to its use for virtual colonoscopy (expiring 2025) and another of which is directed to its use for in vitro diagnostics (expiring 2025). LIGHT is also covered by pending U.S. and European patent applications directed to its use for in vivo diagnostics and once issued should expire in 2025. Lastly, the use of LIGHT for diagnostics purposes with cancer stem cells is pending in the U.S., Europe, and Japan. Patents resulting from these applications are expected to expire in 2030.

HOT is covered by two additional series of our patents and applications aside from the Michigan patents. The first is directed to a method of use for cancer therapy and has also been filed in Europe and Japan, in addition to the U.S. These are expected to expire in 2025. Secondly, an application directed to cancer stem-cell therapy is pending in the U.S., Europe, and Japan. Patents resulting from these applications are expected to expire in 2030. Some of these resulting patents may be extendable on a country-by-country basis.

GLOW2 is covered by patent applications directed to compound, methods of use and method of manufacture that have been filed in U.S., Europe and Japan. Patents resulting from these applications are expected to expire in 2029. Some of these resulting patents may be extendable on a country-by-country basis.

Separate from any patent protection and following product approval by regulatory authorities, data exclusivity may be available for various compounds for up to 10 years on a country-by-country basis (e.g., up to 5 years in the U.S.).

The early termination of the University of Michigan license agreement would result in the loss of our rights to use the covered patents.

In addition to the above noted patents/applications directed to LIGHT, HOT and GLOW2, we own other patents/applications directed to different forms of phospholipid ethers and methods of manufacturing of phospholipid ethers.

We also own all intellectual property rights worldwide (excluding Russia and the other states of the former Soviet Union, the Russian Territory) related to our clinical-stage pipeline compound, NOV-002, and other pre-clinical compounds based on oxidized glutathione. Issued composition-of-matter patents cover proprietary formulations of oxidized glutathione that do not expire until 2019, and these patents include methods of manufacture for oxidized glutathione formulated with various metals.