Whole-body organ-level and kidney micro-dosimetric evaluations of (64)Cu-loaded HER2/ErbB2-targeted liposomal doxorubicin ((64)Cu-MM-302) in rodents and primates.
BACKGROUND
Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predicts therapeutic outcome. In support of a first in-human clinical trial with (64)Cu-labeled HER2-targeted liposomal doxorubicin ((64)Cu-MM-302), a preclinical dosimetric analysis was performed.


METHODS
Whole-body biodistribution and pharmacokinetic data were obtained in mice that received (64)Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of (64)Cu signal in mouse kidneys. Kidney micro-dosimetry analysis was performed in mice and squirrel monkeys, using a physiologically based pharmacokinetic model to estimate the full dynamics of the (64)Cu signal in monkeys.


RESULTS
Organ-level dosimetric analysis of mice receiving (64)Cu-MM-302 indicated that the heart was the organ receiving the highest radiation absorbed dose, due to extended liposomal circulation. However, PET/CT imaging indicated that (64)Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of (64)Cu activity in the renal pelvis. This result was reproduced in primates. Kidney micro-dosimetry analysis illustrated that the renal pelvis was the maximum exposed tissue in mice and squirrel monkeys, due to the highly concentrated signal within the small renal pelvis surface area.


CONCLUSIONS
This study was used to select a starting clinical radiation dose of (64)Cu-MM-302 for PET/CT in patients with advanced HER2-positive breast cancer. Organ-level dosimetry and kidney micro-dosimetry results predicted that a radiation dose of 400 MBq of (64)Cu-MM-302 should be acceptable in patients.
Merrimack Pharmaceuticals, One Kendall Square, Suite B7201, Cambridge, MA 02139 USA.
Daniel F
DF
Gaddy
Merrimack Pharmaceuticals, One Kendall Square, Suite B7201, Cambridge, MA 02139 USA.
Helen
H
Lee
STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 190 Elizabeth Street, Toronto, ON M5G 2C4 Canada.
Jinzi
J
Zheng
STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 190 Elizabeth Street, Toronto, ON M5G 2C4 Canada.
David A
DA
Jaffray
Merrimack Pharmaceuticals, One Kendall Square, Suite B7201, Cambridge, MA 02139 USA.
Thomas J
TJ
Wickham
Merrimack Pharmaceuticals, One Kendall Square, Suite B7201, Cambridge, MA 02139 USA.
Bart S
BS
Hendriks
Copper-64; Dosimetry; Nanotherapeutics; Positron emission tomography