March 15, 2008 (Vol. 28, No. 6)
CLR1404 Represents a New Candidate for Diagnosing and Treating Cancer
Cellectar, an early-stage oncology company, is banking on its radiopharmaceutical technology that combines lipid-like phospholipid ethers (PLE) with radioisotopes of iodine to seek out and destroy solid tumors and monitor the success of treatment. Not surprisingly, the firm’s tagline is “Find. Treat. Follow.”
The company’s technology platform took 15 years to develop in the laboratory of Jamey Weichert, Ph.D. In 2000, Dr. Weichert founded Cellectar and now oversees all research as CSO. Both sophisticated medicinal chemistry and structural activity relationship studies led to Cellectar’s lead molecule, CLR1404.
Imaging studies confirm that CLR1404 selectively accumulates and is retained in 42 solid tumors including breast, prostate, lung, colon, kidney, head and neck, gliomias, and melanomas, Dr. Weichert says. Moreover, preclinical experiments in mouse models of three human cancers (breast, prostate, and lung) show that CLR1404 slows malignant tumor growth and improves mean survival time in tumor-bearing animals.
Novel Molecular Action
For reasons not fully understood, normal cells appear to break down the PLE analog and eliminate it, while tumor cells do not. Low levels of the enzyme phospholipase-D in tumors may account for the preferred retention of PLE by cancer cells.
By synthesizing multiple PLEs with straight backbones of varying alkyl chain lengths, Dr. Weichert’s team learned that chain length is a critical factor for controlling selective tumor uptake and retention. At chain lengths of 7 to 12 carbons, little or no tumor accumulation occurs, and the molecules are rapidly cleared from the body. But increasing the chain length to 15 or 18 carbons enhances tumor uptake and retention. CLR1404 is based on a linear 18-carbon chain.
In addition, the placement of radioactive iodine in CLR1404 prevents in vivo deiodination. Historically, in drugs attached to radioactive iodine, the iodine molecule is naturally released and taken up by the thyroid gland. “With our molecules there is absolutely no free iodine to cause unwanted side effects,” says Bill Clarke, M.D., president and CEO.
CLR1404 offers “an entirely new mechanism for the diagnosis and treatment of malignancy,” notes Dr. Clarke. By attaching one of two different isotopes of iodine, CLR1404 becomes either a diagnostic or therapeutic molecule.
Iodine-131 (131I) is a radioisotope that has been around for 50 years and has been used to treat thyroid cancer. It is also used in some newer drugs like GlaxoSmithKline’s Bexxar (tositumomab), a monoclonal antibody for the treatment of non-Hodgkins lymphoma. “Iodine-131 has been hooked up to other carrier molecules for some time and is a successful treatment,” points out Clarke.
A newer isotope, Iodine -124 (124I ) made in a cyclotron, emits too little radiation to be therapeutic, yet is ideal for use with positron emission tomography (PET) to diagnose tumors and follow their regression or recurrence during and after treatment.
“Iodine-124 labeled CLR1404 will be a good oncology imaging agent,” says Dr. Clarke, because its use in PET scanning will allow for sensitive and specific detection of malignancies, either in primary tumors or undetected metastases. The company’s overall model will be to use 124I-CLR1404 to diagnose cancerous cells, then treat them with 131I-CLR1404, followed by surveillance with 124I-CLR1404 to monitor the response to therapy.
The novel targeted delivery capability of CLR1404 may ease the regulatory route to FDA approval. If a company were investigating monoclonal antibodies to treat 42 different solid tumors, it would be required to file 42 individual IND applications. Instead, a successful Phase I trial proving the safety of CLR1404 in a few solid tumors will be sufficient to support other trials, since the same molecule can treat a variety of solid tumors.
Cellectar will file an IND for CLR1404 in the first quarter of 2008 to evaluate safety and radiation dosimetry. The first patients will likely be those with non-small-cell lung cancer and pancreatic cancer. “Both diseases need new and better ways to treat them,” says Dr. Clarke. Once the therapy appears successful, Cellectar will file an amendment to the IND to add 124I-CLR1404 to monitor tumor shrinkage. “In animal models, 124I-CLR1404 is extraordinarily accurate at telling you how tumors are responding.”
A previous Phase I investigator-initiated trial at the University of Wisconsin in 11 lung cancer patients found that both 124I-CLR1404 and 131I-CLR1404 were taken up by tumors at low doses with no adverse outcomes. Another 10 healthy volunteers, who received unlabeled CLR1404, also showed no adverse effects. This NIH-funded study was conducted without input from Cellectar. Nonetheless, “the molecule has been tested in people and did what we expected it to do without causing toxicity,” remarks Dr. Clarke. “That’s good news and very exciting.”
Throughout the history of oncology treatments, incremental progress based on a given mechanism of action has been common. Occasional leaps in efficacy occur when a new technology comes along, such as microtubule disruptors like the taxanes, monoclonal antibodies like Herceptin for breast cancer, or tyrosine kinase inhibitors.
“We expect another jump in efficacy by exploiting a new biological mechanism—the selected uptake and retention of PLE,” Dr. Clarke says.