Evaluation of CD44v6-targeted radionuclide therapy on bone marrow, skin and esophageal epithelium using a novel internal dosimetry model

<i>Objective</i>. The cell surface antigen CD44v6 is a promising target for several cancers, with favorable<i>in vivo</i>characteristics such as high affinity and suitable biodistribution. In normal tissues, expressions are restricted to basal epithelial cells in skin and mucosa. Consequently, previous clinical studies have reported varying degrees of toxicity in these tissues. To support new radioimmunotherapies (RIT), we developed small-scale internal dosimetry models for abdominal skin and esophageal mucosa. Using published biodistribution data, we compared absorbed doses to epithelial tissues and bone marrow from four clinically relevant radionuclides: rhenium-186, lutetium-177, terbium-161, and actinium-225.<i>Approach</i>. From the Genotype-Tissue Expression database, 288 H&E-stained sections of abdominal skin and esophageal mucosa were obtained from donors aged 21-70 and segmented to generate voxelized models. Monte Carlo simulations were conducted for the radionuclides across multiple source/target combinations. A compartment model generated serum, skin, and bone marrow biodistributions to estimate AD to the epithelium and bone marrow.<i>Main results</i>. Absorbed dose estimates to the basal layer of the skin were highest for¹⁶¹Tb at 23.7 Gy GBq^-1, followed by¹⁷⁷Lu and¹⁸⁶Re, with values of 9.5 and 5.3 Gy GBq^-1, respectively, whereas the alpha emitter²²⁵Ac delivered a dose of 4.9 Gy MBq^-1. For the<i>β</i>-emitters, three methods produced absorbed-dose estimates for the red marrow (RM) consistent within 5% of each other, with the highest values in the hip bone: 0.36, 0.25, and 0.39 Gy GBq^-1for¹⁸⁶Re,¹⁷⁷Lu, and¹⁶¹Tb, respectively, compared to 0.66 Gy MBq^-1for²²⁵Ac.<i>Significance</i>. This study presents a dosimetry framework for CD44v6-targeted RIT, demonstrating that, at clinically relevant administered activities, short-ranged emitters like¹⁶¹Tb and²²⁵Ac deliver substantially higher doses to basal epithelial layers compared to¹⁸⁶Re. RM doses were comparable for¹⁶¹Tb and¹⁸⁶Re, lower for¹⁷⁷Lu, and highly uncertain for²²⁵Ac due to daughter redistribution. Overall, these results support the use of¹⁷⁷Lu for initial clinical trials.