Calando Pharmaceuticals last week released data demonstrating that its lead cancer drug candidate, an siRNA targeting the M2 subunit of ribonucleotide reductase, was well-tolerated at certain doses in non-human primates.
The results were presented by Calando CSO Jeremy Heidel at this year’s Oligonulcotide Therapeutics Society meeting at Rockefeller University in New York.
Last month, the company announced that its first drug-development program would center on an siRNA-based treatment for various solid tumors, and that phase I testing is set to begin before the end of 2007 (see RNAi News, 9/7/2006). At the time, however, the company did not provide specifics about the cancer target it is pursuing beyond stating that it is a gene “implicated in a wide variety of solid tumors.”
At the Oligonucleotide Therapeutics Society meeting, Heidel disclosed that Calando’s lead drug candidate is directed against RRM2, and that it appeared well tolerated when administered in escalating doses using the company’s proprietary delivery technology to non-human primates.
He also said that Calando remains on track to advancing the candidate into the clinic during the second half of next year.
RR is an enzyme that catalyzes the formation of the deoxyribonucleotideprecursors required for DNA synthesis. Heidel said that the RR subunit M2 is well established as a cancer target given its essential role in DNA synthesis and repair, as well as cell proliferation, and that a number of companies are pursuing development of drugs against RRM2, including Lorus Therapeutics, which is evaluating an antisense-based RRM2 inhibitor in a phase II study in advanced or metastatic renal cell carcinoma.
Additionally, “there have been a couple of reports of people achieving knockout of M2 in a particular cancer cell line through an siRNA approach,” Heidel noted during his presentation.
One such report appeared in a paper in the February 2004 issue of Oncogene in which researchers from the Brigham and Women’s Hospital at Harvard Medical School showed that siRNAs targeting RRM2 could boost the effect of the chemotherapeutic gemcitabine and that systemically delivered RRM2 siRNA could suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma.
A few months later, the same team published additional data in Surgery about using siRNA tools to silence RRM2 in cancer.
In light of these and other findings, Calando initiated a pilot study examining the tolerability of an siRNA directed against RRM2 in three female, non-naïve cynomolgus monkeys when delivered in escalating doses of 3, 9, and 27 mg/kg.
The siRNAs were delivered using an in-house delivery technology that comprises a linear, cyclodextrin-containing polycation capable of binding to the anionic backbone of an siRNA. When mixed together, the polymer and siRNA self-assemble into nanoparticles, roughly 50 nanometers in diameter, which are protected from nuclease degradation in blood serum.
According to Calando, the cyclodextrin in the polymer allows stabilizing agents to be attached to the surface of the particles. These agents have terminal adamantane groups that form inclusion complexes with cyclodextrin and contain polyethylene glycol, which prevents aggregation while preventing degradation. Additionally, ligands to cell-surface receptors — in the case of the pilot study, human transferrin — can be covalently attached to the adamantane-PEG modifier, which allows the particles to be targeted to tissues of interest.
Heidel noted that the 3 mg/kg and 9 mg/kg doses were administered through a conventional intravenous injection, but that due to its size the 27 mg/kg dose was delivered as a 2-hour IV infusion.
“There have been a couple of reports of people achieving knockout of M2 in a particular cancer cell line through an siRNA approach.”
After treatment, Calando researchers found no changes in indicators of liver function or “some of the more common” blood counts, according to Heidel. However, there was some indication of renal function impairment associated with the 27 mg/kg dose.
Further, “we did see quantifiable levels of antibodies at day 18 in all three animals,” he said. However, “the levels were pretty modest — about 2 or 3 micrograms per milliliter — [and] well below what we might expect with a strong antibody response.” Further analysis led the researchers to conclude that the antibodies were in response to the human transferrin protein being used as a targeting agent.
Heidel said that pharmacokinetic data were not available in time for his presentation.
The results that were available, he said, “suggest that the lower doses of 3 and 9 mg per kg siRNA were well tolerated … [and] that it will be possible to do repetitive dosing of our formulation.
“We have scaled up manufacturing of all the components that we need for our delivery system, and we’re hoping to start a phase I clinical trial by the end of next year in patients with solid tumors” of multiple origin, Heidel added.
In the meantime, Calando is conducting additional preclinical work, such as biodistribution studies in mice, and developing additional targeting molecules for use with its delivery system, he said.