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Good article on RIGScan...

Biological Retrofits
Posted on May 18, 2011 by meddevice| Leave a comment
A MAb Resurrected!

After more than a decade since the FDA rejected Ohio-based Neoprobe Corp.’s RIGScanTM CR, a monoclonal antibody (MAb) for the detection of colorectal cancer, the company has announced that in Pre-IND talks with the agency, the two have concluded that a new clinical trial can begin in 2012. I recall reporting on the progress of this technology about 15 years ago, but the “radiopharmaceutical” hit a major setback in 1998 when the FDA rejected it because it did not show a clear benefit for patients. Now, 12 years later, that same data that prevented its approval may have been what helped Neoprobe resurrect RIGScan. It appears that Neoprobe has some convincing data from those patients treated well over a decade ago. Treated patients had significantly higher survival rates over the ensuing years compared to patients who did not have RIGScan-tagged tissue surgically removed.

RIGScan CR is a MAb that targets a telltale colorectal cancer marker called TAG-72, which is also common in many epithethelial cell-derived tumors, including some breast tumors, invasive ductal tumors, non-small cell lung tumors, epithelial ovarian tumors, and the majority of gastric, pancreatic and esophageal cancers. So, the treatment holds great promise beyond colorectal cancers. The “radiopharmaceutical” is tagged with a radioisotope that is used for detection only, not direct therapy. Once bound to the tumor cells that may have lingered following surgery, a hand-held radiation detection device made by Neoprobe helps surgeons hone in on the cells and remove them before they repopulate.

You may be asking why you’re reading about a radiopharmaceutical in a MedTech blog, which I’m happy to explain after a brief review of MAb technology: Antibodies are the immune systems sentinel soldiers. When a pathogen enters the body, antibodies are generated to bind unique surface features on the foreign tissue. Once bound, a signal is sent to other components of the immune arsenal, including neutrophils, lymphocytes (killer T cells) and many others to mount the attack on the pathogen flagged by the antibody. Despite their nanoscale, viruses and bacteria have many unique surface features, called antigens, often consisting of different sugar and lipid molecules. (Think of facial features: more than 6 billion people and everyone unique.) The same is true for tumor cells. They have surface features that differ from healthy non-malignant cells, as well as surface features that vary among malignant tissue types.

When it encounters a virus or bacteria, the immune system will generate antibodies that recognize many of these unique surface features, not just one. Antibodies are shaped like the letter “Y.” The clef of the “Y” contains the Antigen Binding Site (ABS), which is very much like a lock that can only be engaged by the specific “key” or antigen on the pathogen.

Monoclonal antibodies are highly engineered molecules that bind to only one antigen. This is no small achievement. The process involves fusing myeloma cells with mouse spleen cells. The resulting is an immortal cell line (myeloma) that produces antibodies (spleen cells). By immunizing this little antibody factory with a single target antigen, the cell line produces antibodies that identify one very specific antigen. Of course, the process is not this clean. Different hybrid cells produce slight variants of the ideal antibody. A filtering and selection process helps find the ideal hybrid clone or “hybridoma,” which is cultured and used to pump out millions of identical antibodies of near-perfect specificity for the target antigen.

Since these molecules are of mice but for men (and women), another step in the process is required to make the molecules more human. Remember, the human immune system is designed to recognize and destroy all non-human invaders, so MAbs that are mostly murine (mouse), will themselves be targeted by the immune system. This is called HAMA for human anti-mouse antibodies, which are generated and target the MAbs and render them therapeutically useless. So, another recombination step is required to replace the large murine structural regions of the MAb with human components.

So (if I haven’t lost you yet), I write about these tiny cancer-seeking, radiolabled clones because they are more engineered than any artificial joint or pacemaker that I can think of. In fact, it’s hard to imagine a more machined medical device than these macromolecules.

However, to be fair, when mice spontaneously generate half-man-half-mouse-human-cancer-detecting antibodies that serendipitously happen to be flagged with isotopes that make them easy to spot for surgeons in the process of removing hidden colorectal tumor cells, I’ll stop writing about these molecules.

According to Rodger Brown, vice president, Regulatory Affairs and Quality Assurance of Neoprobe, “We have clarified the path to reinitiate RIGScan development and the requirements for resuming development activities and moving toward clinical trials. FDA’s guidance has provided direction to enhance our manufacturing platform, including process improvements to increase manufacturing efficiency and the quality of the underlying biologic antibody. We can now begin to implement our manufacturing plans through 2011 as a first step to recommencing clinical study of the technology in 2012 and beyond.”

In one small trial, including five patients with recurrent colorectal cancer, traditional exploration for remaining tumor cells turned up 17 sites determined to be suggestive of recurrence. These sites included the colon and rectum, as well as the abdominal wall, Iliac lymph nodes and inferior vena cava. In the same patient population, 14 positive sites were identified, and six additional positive sites, which were missed by traditional detection, were uncovered. The traditional method had a specificity of 64 % and positive predictive value of 90%, while RIGScan provided 92% sensitivity and 100% positive predictive value. None of the patients had a HAMA reaction to RIGScan CR.

Of course, much larger studies are required, but this is a very positive development for cancer patients and a Dublin Ohio biotech company that wouldn’t take no for an answer.

http://medtechintel.com/