By Doug Macron
Oncology drug developer Immunomedics this week presented in vitro data showing that a proprietary antibody-based delivery technology can create a protein complex capable of trafficking siRNAs into cancer cells.
The company does not anticipate using the approach to develop RNAi-based drugs itself, but rather hopes to out-license it to a partner interested in taking it forward into the clinic, an Immunomedics spokesman told RNAi News.
According to the company, the complex was created using its so-called dock-and-lock, or DNL, technology, which uses "the natural interaction" between cyclic AMP-dependent protein kinase and A-kinase anchoring proteins.
"The basic strategy of DNL involves the generation of two types of modules, one containing the dimerization and docking domain of cAMP-dependent protein kinase and the other containing the anchoring domain of a related A-kinase anchoring protein," according to a poster the firm presented at this year's American Association for Cancer Research annual meeting in Washington, DC.
"Docking a DDD-containing module with an AD-containing module occurs spontaneously, and the resulting complex is locked with disulfide bonds to enhance in vivo stability," the abstract notes.
In order to develop an siRNA-delivery vehicle, Immunomedics said it used the DNL platform to join the humanized monoclonal antibody hRS7; a proprietary humanized antibody targeting TROP-2, a cell-surface glycoprotein expressed by certain cancers; and four copies of human protamine, which are small proteins capable of binding to nucleic acids.
The resulting complex, termed E1-L-thP1, was found to internalize in cells expressing the TROP-2 antigen, "suggesting the binding ability of hRS7 remains intact in the fusion protein," the company said. It also "effectively delivered siRNAs into TROP-2-expressing cancer cells, causing cell death."
Chau Cheng, associate director of investor relations and business analysis at Immunomedics, said that thus far, the company has only examined the siRNA-delivery potential of the DNL technology in vitro. He added that the company is examining its efficacy with siRNAs against a variety of other targets.
Specifically, Immunomedics is evaluating in vitro and in vivo whether E1-L-thP1 can deliver siRNAs against the tumor-associated genes CD74 and CEACAM6 in TROP-2-expressing pancreatic cancer cells, the company said.
Immunomedics, Cheng noted, views this work as a sort of proof of concept that could lay the groundwork for licensing deals with companies interested in using the delivery approach in their own RNAi-based cancer drug programs, rather than forming the basis for in-house programs.
DNL is "a platform technology that has such wide applicability, I don't think we can do everything," he said. When it comes to RNAi, "our goal is to license the dock-and-lock technology on a non-exclusive, project-by-project basis."
Immunogenics isn't the only company looking to use protamine-conjugated antibodies for siRNA delivery.
Bioo Scientific has long been selling antibody-protamine conjugates for siRNA delivery for research applications. Late last year, it began selling its T3 conjugation kit for targeted in vivo delivery of siRNAs and other RNAi molecules, which also uses the protein to bind the oligos to an antibody specific to a targeted cell or tissue type.
In addition, the company's subsidiary Bioo Therapeutics is examining whether this technology can be used for therapeutic RNAi applications.
This week, Lance Ford, Bioo's vice president of research and development, told RNAi News that his company continues to market reagents that incorporate protamine, but that it has also been experimenting with other positively charged proteins capable of linking siRNAs to antibodies.
At the same time, Bioo is developing proprietary linkers that may allow for the direct conjugation of RNAi payloads with targeting antibodies, something that could potentially increase the loading capacity of the delivery vehicles, he added.
And back in 2005, Harvard University researcher Judy Lieberman and colleagues reported in Nature Biotechnology how they created a protamine-antibody fusion protein capable of delivering siRNAs to HIV-infected or envelope-transfected cells.
Lieberman's technology was previously non-exclusively licensed by Alnylam Pharmaceuticals (RNAi News 5/11/2006), although that company is currently focused on using lipid-based delivery approaches within its drug-development programs.
Lieberman told RNAi News this week that her antibody-delivery technology is also currently under evaluation by an undisclosed "large pharmaceutical company."