Critical evaluation of bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when 10B, a stable isotope, is irradiated with low energy neutrons to produce high linear energy transfer (LET) alpha particles and recoiling 7Li nuclei. In order for BNCT to be successful in treating cancer, approximately 10(9) boron atoms must be delivered per tumor cell to sustain a lethal 10B, (n,a) 7Li capture reaction. In the present study, we have produced and characterized a bispecific antibody (BsAbB8), which was reactive with both human glioma and melanoma cell lines, as well as with a variety of polyhedral borane anions (PBA). The affinity constants (KA) of BsAb-B8 with D-54 MG and M21 cells were 3.49 and 2.57 x 10(8) M-1, respectively, which were almost identical to those of the parental mAb 9.2.27 with these cell lines. In vivo tumor localizing properties were studied in nude mice bearing subcutaneous xenografts of the D-54 MG glioma. Following intravenous injection of 131I-labeled BsAb-B8, 3.4 +/- 0.2% of the injected dose/g was detected in the tumor at 24 hours, and then slowly declined to 2.0 +/- 0.4% at 96 hours compared to 1.34 +/- 0.07% and 0.03 +/- 0.01%, respectively, for normal mouse IgG. Based on the assumption that all the tumor cell antigenic receptor sites could be saturated, the following calculations have been carried out. The maximum concentration of BsAb-B8 that could be delivered to 1 g of D-54 MG glioma cells would be 99.6 micrograms, which could bind 71.7 ng of a PBA. However, since at least 500 x more boron would be required per gram of tumor to sustain a lethal 10B (n,a) 7Li capture reaction, a macromolecule containing -10(3)-10(4) boron atoms rather than a low molecular weight PBA would be required to deliver this amount. Such boron containing macromolecules have been synthesized by us, and future studies should provide information on the feasibility of using them in combination with BsAb-B8 to deliver the requisite amount of 10B.