In the late 1990s, M.D. Anderson recognized the need for an alternative molecular imaging technology that could overcome the issues specific to FDG-PET. This led to the creation of EC- Technology. Cell>Point licensed the technology from MD Anderson, reformulated it from its original inorganic aqueous form to an organic compound to improve its CMC profile, chemical purity, production yield and chelation properties and created Oncardia. Oncardia’s drug conjugate technology functions as a highly stable chemical bridge linking tissue specific ligands (sugar analogues, proteins, peptides, steroids, etc.) or pharmaceutical compounds to radioisotopes (hot or cold) for diagnostic and therapeutic purposes.
The majority of nuclear molecular imaging agents are either produced in a cyclotron creating logistical issues or they use multi-vial kits creating quality control issues. A one vial kit eliminates both logistical and quality control issues.
Deoxyglucose will uptake in inflammation and infection resulting in false positives. Oncardia uses glucosamine to mimic N-Acetyl Glucosamine with minimal uptake in neutrophils and macrophages, thereby minimizing uptake in infection / inflammation reducing false positives. Using this different sugar analog makes Oncardia an excellent agent to image many forms of cancer in addition to ischemia.
Cell>Point is completing a Phase 3 trial for lung cancer imaging under an FDA Special Protocol Assessment and completed a physician IND study for head and neck cancer. In addition to lung cancer, Cell>Point plans to complete trials for head and neck, breast, lymphoma, liver, prostate, colorectal and kidney cancer.
First, Oncardia can be used to image cancer on both PET and SPECT cameras. The advantages of imaging on SPECT cameras is access, lower cost and reduced radiation exposure. Currently the US has over 15,000 installed SPECT cameras compared to just over 2,400 installed PET cameras. Over 90% of worldwide hospitals have a SPECT camera. SPECT imaging reduces radiation exposure by 73% and the overall cost of SPECT imaging is on average 30% less than PET.
Oncardia enters the cell through Glut 1 and 3 receptors and is involved in intracellular glycosylation. FDG also enters the cell through Glut 1 and 3 receptors and is phosphorylated by hexokinase II to become F-18-FDG-Phosphate. F-18-FDG is missing the 2-hydroxyl group that is needed for further glycolysis. Hence, FDG is trapped in the cell cytoplasm, a process known as “metabolic trapping”. When Oncardia enters a diseased cell, it is picked up by the Hexosamine Biosynthetic Pathway and O-linked glucosamine transferase (OGT), which are only active when the cell is in a diseased state. OGT is a key enzyme Isilent oncogene for glycosylation during cancer revolution. As a glycoprotein, Oncardia then translocates through the cell membrane into the cell nucleus – creating an ideal platform for targeted diagnostics and therapeutics. Oncardia’s translocation into the nucleus drives uptake independent of glucose, yielding improved diagnostic accuracy in the presence of inflammation/infection.
Philips Healthcare developed Astonish software with the help of Cell>Point to optimize Tc-99m-Oncardia images. The algorithms used in the Astonish software are on most of the SPECT cameras used in the US, Europe and Asia. The Astonish software allows for more accurate calculation of dosimetry (mass of the primary and secondary lesion) which allows for Oncardia to measure response to therapy as soon as 4 weeks.
It was observed during oncology imaging trials that 99mTc-Oncardia localized in the area of the myocardium where ischemia was present. What was further found was that 99mTc-Oncardia exhibited very low uptake in the normal unaffected part of the myocardium. This suggested that 99mTc-Oncardia might also be a potential functional imaging agent for cardiovascular disease. Unlike current nuclear cardiology imaging agents that image blood flow and generally requires two separate studies, one for stress and the other for rest and can take 4-5 hours to complete, Oncardia does not image blood flow, eliminating the need for an image at stress in majority of patients. Phase 1b/2a studies for Oncardia imaging for cardiology showed diagnostic accuracy of 95% compared to current MPI cardiology imaging agents that have a diagnostic accuracy of 72%.
Oncardia has been shown to have ischemic memory capabilities. Basically, once glucose depletion is adequate to turn on the Hexosamine Biosynthetic Pathway, the ischemia is detectable until the glucose depletion returns to normal. Thus, Oncardia can detect ischemia from the moment a cardiac event occurs until the heart returns to normal function.
CARDIAC APPLICATIONS (Estimated Procedures Per Year)
The presence of CAD does not equate to myocardial disease (ischemia). Rather, Oncardia is metabolized in the nucleus of the cell and is target specific for ischemia if the CAD is sufficient to cause ischemia. Typically, the degree of stenosis needs to be >70 %. However, it is possible that ischemia will be present in patients with a lower degree of stenosis if they have a chronic myocardial disease such as CHF. Such patients could be successfully imaged for ischemia for any degree of flow restriction.
For cardiac applications, the following patient groups will benefit the most:
Platinum-Oncardia for the treatment of aggressive type B lymphoma, lung cancer and head and neck cancer. Next, 177Lu-Oncardia. Cell>Point has been completing pre-clinical research on Platinum-Oncardia at the University of Texas M.D. Anderson Cancer Center for aggressive type B lymphoma and has shown advantages of Platinum-Oncardia over traditional platinum chemotherapy. These advantages include a much lower dose of platinum (10-15 mg) compared to 400 mg of Cisplatin and significant lower side effects.
The refence standard for Platinum-Oncardia is Cisplatin or oxaliplatin that does not have an active transport system. Platinum-Oncardia should be the first-in-class water soluble platinum drug to target OGT in hexosamine pathway-directed therapy. The MOA of delivering Platinum-Oncardia is the same as 99mTc-Oncardia. The patient would first be imaged with 99mTc-Oncarida which will provide the dosimetry of the primary and secondary lesion. The dose of Platinum-Oncardia would be calculated by the dosimetry number and the patient’s weight. Using this targeted system should enable 90% plus of the platinum to go to the cancer cells not healthy cells. The patient would be imaged after 4 weeks. Using the dosimetry calculation, the oncologist can accurately determine the patients’ response to Platinum-Oncardia therapy and if that patient should receive another dose of Platinum-Oncardia or move to a different therapeutic.
Cell>Point is using the same Oncardia theranostic model with our beta cell conjugate technology. Using of beta-cell mapping DTPA, 99mTc-DTPA-Nateglinide is being used to image and monitor the insulin-receptor function in pancreatic beta cells for the early diagnosis of pancreatic diseases, diabetes, cancers and evaluation of therapeutic responses.177Lu- DTPA-Nateglinide is being used to conjugate water soluble 177Lu- to insulin receptors to pancreatic and neuroendocrine carcinoma with minimum damage to healthy cells. Cell>Point is also working with the University of Chicago Medical Center to study 99mTc-DTPA-Glipizide to evaluate its ability to distinguish Type I and Type II diabetes.
N4 Technology is being used to develop new SPECT as well as a new class of PET imaging agents that will be labeled with generator-based radioisotopes (as opposed to cyclotron-based radioisotopes such as 18F that is currently the radioisotope used with FDG). The company believes that generator-based radioisotopes will be more cost effective and provide greater flexibility in the development of new agents. The first product under development is a SPECT imaging agent, 99mTc-N4-Tyrosine. This product will be used to assess tyrosine kinase activity to help determine which patients with lung or breast cancer, for example, will benefit from anti-EGFR-tyrosine kinase therapy. In addition, N4 Technology compounds are being evaluated for imaging and treating neuroendocrine tumors and for diagnosing, assessing and potentially treating patients with Parkinson’s, Huntington’s and Alzheimer’s as well as certain other diseases affecting the central nervous system. In 2016, Vyripharm Biopharmaceuticals licensed the use of the N4 Technology from the company to be used with cannabidiol/cannabinoids in neurological disorders including epilepsy, and PTSD.