Bone marrow RBE for a 212Pb-conjugated anti-HER2/neu antibody

Introduction: We have determined the in vivo relative biological effectiveness (RBE) of an alpha-particle emitting radiopharmaceutical therapeutic (αRPT) agent (²¹²Pb-labeled anti-HER-2/neu antibody) for the red marrow, a potentially dose-limiting normal tissue.

Methods: The RBE was measured in mice using marrow cellularity as the biological endpoint. External beam radiotherapy (EBRT), delivered by a small animal radiation research platform was used as the reference radiation. Alpha-particle emissions were delivered by ²¹²Bi, following the decay of its parent nuclide ²¹²Pb, conjugated onto an anti-HER2/neu antibody. The alpha-particle absorbed dose to the marrow following intravenously administered (tail vein) 122.1-921.3 kBq ²¹²Pb-TCMC-7.16.4 was calculated. Mice were sacrificed at 0-7 days post-treatment and femur bone marrow was counted for radioactivity. Changes in marrow cellularity were assessed histopathologically.

Results: The dose-response for EBRT and ²¹²Pb-anti-HER2/neu antibody were linear-quadratic and linear, respectively. By transforming the EBRT dose-response relationship into a linear relationship using the EQD2 formalism we obtain an RBE (denoted RBE2) of 6.4; this value is independent of cellularity and absorbed dose.

Conclusions: Since hematologic toxicity is dose-limiting in almost all antibody-based RPT, in vivo measurements of RBE are important in helping identify an initial administered activity (AA) in phase 1 escalation trials. Applying the RBE2 and assuming typical antibody clearance kinetics (Biological half-life of 48 h) with a modified blood-based dosimetry method, an AA of approximately 185.5 MBq (5.0 mCi) may be administered before hematologic toxicity is anticipated.