CRITICAL-EVALUATION OF BISPECIFIC ANTIBODIES AS TARGETINS AGENTS FOR BORON NEUTRON-CAPTURE THERAPY OF BRAIN-TUMORS

Boron neutron capture therapy (BNCT) is based on the nuclear capture r eaction that occurs when B-10, a stable isotope, is irradiated with lo w energy neutrons to produce high linear energy transfer (LET) alpha p articles and recoiling Li-7 nuclei. In order for BNCT to be successful in treating cancer, similar to 10(9) boron atoms must be delivered pe r tumor cell to sustain a lethal B-10, (n,alpha) Li-7 capture reaction . In the present study, we have produced and characterized a bispecifi c antibody (BsAb-B8), which was reactive with both human glioma and me lanoma cell lines, as well as with a variety of polyhedral borane anio ns (PBA). The affinity constants (K-A) of BsAb-B8 with D-54 MG and M21 cells were 3.49 and 2.57 x 10(8) M(-1), respectively, which were almo st identical to those of the parental mAb 9.2.27 with these cell lines . In vivo tumor localizing properties were studied in nude mice bearin g subcutaneous xenografts of the D-54 MG glioma. Following intravenous injection of I-131-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 follo wing 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 b e 99.6 mu g, which could bind 71.7 ng of a PBA. However, since at leas t 500x more boron would be required per gram of tumor to sustain a let hal B-10 (n,alpha) Li-7 capture reaction, a macromolecule containing s imilar to 10(3)-10(4) boron atoms rather than a low molecular weight P BA would be required to deliver this amount. Such boron containing mac romolecules have been synthesized by us, and future studies should pro vide information on the feasibility of using them in combination with BsAb-B8 to deliver the requisite amount of B-10.