Pretargeting method may improve radioimmunotherapy of cancer

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Pretargeting radioimmunotherapy with a trivalent bispecific monoclonal antibody, when compared to a directly radiolabeled antibody, improved anti-tumor responses with less toxicity in a human non-Hodgkin's lymphoma model, according to results presented at the 2008 annual meeting of the American Association for Cancer Research (AACR) in San Diego this week.

RAIT was developed by IBC Pharmaceuticals, a majority-owned subsidiary of the Morris Plains, N.J.-based Immunomedics.

In traditional RAIT, radioisotopes are linked directly to antibodies and are delivered together to tumor targets.  Pretargeting RAIT involves a separate delivery of radioisotope, which is given after the administration of a bsMAb. Because of the time lag, when the therapeutic isotope is administered, the amount of bsMAb is reduced in the blood and normal tissues and is preferentially bound to the tumor, which allows a higher delivery of radiation to the tumors without increased toxicity to normal tissues, Immunomedics said.

Mice bearing human non-Hodgkin's lymphoma transplants were used in the study. For pretargeting, TF4, a trivalent bsMAb with dual binding to the CD20 antigen and monovalent binding to a histamine-succinyl-glycine (HSG) hapten was used. Targeted radiation was delivered as the yttrium-90-labeled HSG-peptide. This was compared to yttrium-90-labeled veltuzumab, a direct targeting anti-CD20 humanized monoclonal antibody developed by Immunomedics. 

According to the results, whole body clearance of yttrium-90 from the pretargeted group was much more rapid than the direct targeting group. In pretargeting, less than 10 percent of the injected dose remained in the body within a few hours. In contrast, the direct targeting group had over 50 percent of radioactivity in the body at two days, the company said. 

At the same time, the levels of radioactivity in tumors were higher in the pretargeted than in the direct-targeting animals. In pretargeting, maximum tumor uptake occurs within one hour, with tumor/blood ratios greater than 20:1 at three hours. The tumor uptake with the yttrium-90-labeled veltuzumab was less than the blood level for more than three days, according to Immunomedics.

The researchers of the study concluded that pretargeted yttrium-90 labeled HSG-peptide was highly effective in controlling tumor growth and eliciting cures in animals with well-established lymphoma transplants, even at the low dose of 0.15 mCi. At the highest dose tested of 0.70 mCi, 90 percent of the tumors were completely ablated, with no severe treatment-related toxicity observed over 20 weeks. While tumors partially responded to doses of 0.15 mCi of the yttrium-90-labeled veltuzumab, most tumors quickly regrew.  Moreover, severe toxicity was observed in 8/20 animals within the first three weeks, and no cures were noted.