Abstract 5350: RBE, in vivo, for a 212Pb-conjugated anti-HER2/neu antibody

Abstract

Abstract The relative biological effectiveness is defined as the absorbed dose ratio (Dref(x)/Dtest(x)) of a reference radiation, Dref, to a test radiation, Dtest, that leads to a particular biological end-point, x. The majority of reported RBE values are obtained from in vitro irradiation of cells in monolayer culture wherein clonogenic survival is the end-point. As alpha-particle emitter radiopharmaceutical therapy (RPT) becomes a viable cancer therapy modality, RBE determinations, in vivo, are essential to assessing the potential efficacy and toxicity of alpha-emitter RPT. The aim of the study was to obtain the relative biological effectiveness, RBE, for alpha-particle emissions delivered by Bi-212, following the decay of Pb-212, conjugated onto an anti-HER2/neu antibody. Photon irradiation (200 kVp, 13 mA, 4 Gy/min, 10 × 10 mm2 collimator), delivered by a small animal radiation research platform (SARRP) was used as the reference radiation to irradiate the femurs of 6-8 weeks old female, neu/N transgenic mice (MMTV-neu). The biological endpoint was the reduction in hematopoietic cells in the region of the femur used for the RBE calculation. Alpha-particle emissions were delivered to this region by administering 325 kBq (8.8 μCi) of 212Pb-TCMC-7.16.4 intravenously (tail vein). Mice were sacrificed (n=3) at 1-7 days post-212Pb-TCMC-7.16.4 antibody administration. The long bones (femurs) were harvested, fixed with formalin and counted for radioactivity. The samples were also examined for histopathologic changes to assess the marrow cellularity. Clinical chemistry and hematological analysis were also performed on blood collected by cardiac puncture. The nadir in blood counts was observed 5 days after radiolabeled antibody injection. An absorbed dose to the marrow from the 212Bi alpha-particle emissions of 1.6 Gy yielded a marrow cellularity reduction of 50 %. The absorbed dose from XRT to achieve the same reduction in marrow cellularity was 5.7 Gy. This gives an RBE of 3.6 for a 212Pb-anti-HER2/neu antibody. Since hematologic toxicity is dose-limiting in almost all antibody-based RPT, in vivo measurements of RBE are critical to avoiding it. 2 Gy to the red marrow of low LET radiation is a threshold between low platelet toxicity grades (1 and 2) vs high (3 and 4) grade toxicity. These results suggest that the toxicity threshold for a 212Pb-antibody would be less than 1 Gy. Citation Format: Ioanna Liatsou, Anders Josefsson, Angel Cortez, Robert F. Hobbs, Cory Brayton, Julien Torgue, George Sgouros. RBE, in vivo, for a 212Pb-conjugated anti-HER2/neu antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5350.