Radioimmunotherapy with ²¹³Bi Targeted to Blood Vessels

  Treatment of cancer with radioimmunotherapy (RIT [radioisotopes coupled with specific antibodies]) has been under development for over 20 years. Clinical trials of RIT for blood-borne diseases are promising, but progress on solid tumors (mainly carcinomas) has been slow. The main limitations have been the slow and inefficient accumulation of antibodies at tumor sites outside of the vascular space.

  Several approaches have been instituted to solve these problems. Stephen J. Kennel, Life Sciences Division, ORNL, has used the approach of employing antibodies that bind inside the lumen of blood vessels that service tumor cells. It has been shown that antibody to vascular targets accumulate rapidly and to very high levels.

  The high efficiency of vascular targeting facilitates novel approaches of RIT. Kennel has employed a model tumor system for solid tumor therapy that uses targeting MAbs coupled to the short half-lived alpha emitter, ²¹³Bi. EMT-6 mammary carcinoma cells are injected i.v. into Balb/c mice. The cells form lung colonies or "artificial metastases" and, if left untreated, progress to kill the mice after 10-14 days. In collaboration with Dr. Saed Mirzadeh of the LSD's Nuclear Medicine Group, ²¹³Bi has been attached to two MAbs that "home" specifically to lung blood vessels.

  The advantage of these antibodies is that a large fraction (>50%) of the dose of ²¹³Bi attaches to the lung within minutes of injection. This maximizes the dose of high-LET particles emitted from the short half-life (T_1/2=46 min) isotope to the target organ. Injection of this radiolabeled MAb has been shown to destroy the experimental tumors in every animal tested to date. All animals treated with moderate doses of RIT have survived more than two months, while all mock-treated control animals succumbed to their tumors within 20 days.

  These preliminary results are being followed up with studies on optimal doses and dose schedule, mechanism of the therapy, and effectiveness for other tumors in the lung.

Contact: Stephen J. Kennel
Telephone: 423-574-0825
E-mail: sj9@ornl.gov