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

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Abstract Objective . The cell surface antigen CD44v6 is a promising target for several cancers, with favorable in vivo 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. Approach . 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. Main results . Absorbed dose estimates to the basal layer of the skin were highest for 161 Tb at 23.7 Gy GBq −1 , followed by 177 Lu and 186 Re, with values of 9.5 and 5.3 Gy GBq −1 , respectively, whereas the alpha emitter 225 Ac delivered a dose of 4.9 Gy MBq −1 . For the β -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 −1 for 186 Re, 177 Lu, and 161 Tb, respectively, compared to 0.66 Gy MBq −1 for 225 Ac. Significance . This study presents a dosimetry framework for CD44v6-targeted RIT, demonstrating that, at clinically relevant administered activities, short-ranged emitters like 161 Tb and 225 Ac deliver substantially higher doses to basal epithelial layers compared to 186 Re. RM doses were comparable for 161 Tb and 186 Re, lower for 177 Lu, and highly uncertain for 225 Ac due to daughter redistribution. Overall, these results support the use of 177 Lu for initial clinical trials.

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