Vascular Targeting of alpha-emitters for Solid Tumor Therapy (October 1999)

Drs. Steve Kennel and Saed Mirzadeh, researchers in ORNL’s Life Sciences Division, have used MAb 201B to murine thrombomodulin to target alpha-emitting radioisotopes to murine lung endothelium. Small tumor colonies (2000 cells) growing in the lung as a result of i.v. injection of EMT-6 mammary carcinoma cells are cured when as little as 50 µCi of 213Bi MAb 201B is injected i.v. This vascular targeted radioimmunotherapy (VT-RAIT), is also effective at killing human tumor colonies growing in the lungs of SCID mice. Larger lung colonies (5000 cells) can be destroyed using VT-RAIT with 90Y (beta--emitter, t1/2 = 64 hr) MAb 201B or a combination of 213Bi MAb 201B VT-RAIT followed by 213Bi or 90Y MAb 13A RAIT. Using a new chelator, HEHA, 225Ac ( alpha-emitter, t1/2 = 10 days) bound to MAb 201B can be targeted effectively to lung endothelium (~300% ID/g) where it is only very slowly released with a t1/2 of 49 hr. This VT-RAIT treatment which has the potential to deliver the same alpha-particle dose, but at a lower dose rate kills tumors, but results in unacceptable radiotoxicity. However, the method of coupling of 225Ac through HEHA to MAb or other targeting agents opens new possibilities for delivering 225Ac, which emits 4 alpha-particles per decay chain, directly to solid tumors for RAIT. In addition, 211At (alpha-emitter, t1/2 = 7.2 hrs) has been coupled to MAb 201B with the SAPS linker. This conjugate effectively delivers 211At to the lung and can cure tumors with injected doses of 5.0 uCi/mouse. It has no apparent acute toxicity at the doses tested (20 uCi/ mouse) and shows great promise for this type of radioimmunotherapy. These experiments show that VT-RAIT with alpha emitting radioisotopes is an effective means of therapy of small tumors. It is hypothesized that damage to the tumor vessels as well as damage to the tumor cells themselves contribute to the therapy. VT-RAIT should be an important therapeutic approach for treatment of metestases of solid tumors in humans when appropriate targeting agent become available. In recognition of this innovative research, Drs. Kennel and Mirzadeh were recently awarded the first annual Life Sciences Division Scientific Achievement Award. (Contact: S. J. Kennel, 574-0825 or sj9@ornl.gov; Funding Source: DOE-KP)