Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody

Ioanna Liatsou; Anders Josefsson; Jing Yu; Zhi Li; Kaori Davis; Cory Brayton; Hao Wang; Robert F Hobbs; George Sgouros

doi:10.1016/j.ijrobp.2023.06.003

Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody

Int J Radiat Oncol Biol Phys. 2023 Nov 15;117(4):1028-1037. doi: 10.1016/j.ijrobp.2023.06.003. Epub 2023 Jun 17.

Authors

Ioanna Liatsou¹, Anders Josefsson², Jing Yu³, Zhi Li³, Kaori Davis⁴, Cory Brayton⁴, Hao Wang⁵, Robert F Hobbs⁶, George Sgouros³

Affiliations

¹ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: [email protected].
² Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
³ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁴ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁵ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

PMID: 37331568
DOI: 10.1016/j.ijrobp.2023.06.003

Abstract

Purpose: In this study we determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium 225 (²²⁵Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity.

Methods and materials: Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0 to 16.65 kBq of the alpha-particle emitter labeled antibody, ²²⁵Ac-DOTA-7.16.4, and euthanized at 1 to 9 days after treatment. Complete blood counts were performed. Femurs and tibias were collected, and bone marrow was isolated from 1 femur and tibia and counted for radioactivity. Contralateral intact femurs were fixed, decalcified, and assessed by histology. Marrow cellularity was the biologic endpoint selected for RBE2 determination. For the reference radiation, both femurs of the mice were photon irradiated with 0 to 5 Gy using a small animal radiation research platform.

Results: Response as measured by cellularity for the alpha-particle emitter RPT (αRPT) RPT and the external beam radiation therapy were linear and linear quadratic, respectively, as a function of absorbed dose. The resulting dose-independent RBE2 for bone marrow was 6.

Conclusions: As αRPT gains prominence, preclinical studies evaluating RBE in vivo will be important in relating to human experience with beta-particle emitter RPT. Such normal tissue RBE evaluations will help mitigate unexpected toxicity in αRPT.