A two‐antibody model for copper‐64 radioimmunotherapy: biodistributions and tumor dosimetry in a mouse model of cancer

Objectives: We previously presented preliminary data on pilot biodistributions of 64Cu‐labeled monoclonal antibodies (mAbs). 1 The purpose of the present studies was to obtain comprehensive biodistributions using a two‐antibody model for direct comparison of an internalizing and a non‐internalizing mAb in the same animal model of cancer. These studies will allow evaluation of the efficacies of the two 64Cu‐labeled mAbs for radioimmunotherapy (RIT) and are part of a larger, ongoing project examining the unusual tumoricidal properties of internalized 64Cu. Methods: DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) was conjugated to an internalizing antibody, cBR96, and a non‐internalizing antibody, cT84.66. Biodistributions of the 64Cu‐labeled conjugates in nude mice bearing LS174T human colorectal carcinoma xenografts were obtained at time points from 15 min to 48 h. Mouse tumor dosimetry was calculated using a Monte Carlo N‐Particle Transport Code. Results: The 64Cu‐DOTA‐cBR96 conjugate demonstrated rapid tumor uptake, reaching 20.2% injected dose per gram of tissue (% ID/g) at 3 h and peaking at 35.4% ID/g by 24 h. Tumor accumulation of 64Cu‐DOTA‐cT84.66 was more gradual, 8.19% ID/g at 3 h (p = 0.002), and reached 43.8% ID/g by 24 h, but maximum uptake was not statistically different from 64Cu‐DOTA‐cBR96 (p = 0.05). Liver, spleen, and kidney uptakes were statistically similar at 24 h for both conjugates (p = 0.05). Tumor absorbed radiation doses were estimated to be 1128 rad/mCi for 64Cu‐DOTA‐cBR96 and 1409 rad/mCi for 64Cu‐DOTA‐cT84.66. Conclusion: The biodistributions and tumor dosimetry of these two radiolabeled antibodies were sufficiently similar for direct comparison of the therapeutic efficacies of internalizing versus non‐internalizing 64Cu RIT agents in the same animal model of cancer. RIT studies using this two‐antibody model are currently in progress to test the hypothesis that internalization of 64Cu is necessary for enhanced cytotoxic properties at low tumor absorbed doses.