Abstract
Background: CD73 is an ectonucleotidase regulating extracellular adenosine concentration and plays an important role in adenosine-mediated immunosuppressive pathways. The efficacy of CD73-targeted therapy depends on the expression levels of CD73; therefore, monitoring CD73 status in cancer patients would provide helpful information for selection of patients who would benefit from CD73-targeted therapy. Here, we evaluated the ability of 111In-labeled antibody 067-213, which has high affinity for human CD73, to act as a noninvasive imaging probe. Methods: Cell binding and competitive inhibition assays for 111In-labeled 067-213 were conducted using MIAPaCa-2 (high CD73 expression) and A431 (low CD73 expression) cells. For in vivo assessments, biodistribution and SPECT/CT studies were conducted in MIAPaCa-2 and A431 tumor-bearing mice. To estimate the absorbed dose in humans, biodistribution and SPECT/CT studies were conducted in healthy rats. Results: 111In-labeled 067-213 bound to MIAPaCa-2 and A431 cells in a CD73-dependent manner and the affinity loss after 111In-labeling was limited. Biodistribution and SPECT/CT studies with 111In-labeled 067-213 in mice showed high uptake in MIAPaCa-2 tumors and lower uptake in A431 tumors. In rats, the probe did not show high uptake in normal organs, including endogenously CD73-expressing organs. The estimated absorbed doses in humans were reasonably low. Conclusions: 111In-labeled 067-213 showed CD73-expression-dependent tumor uptake and low uptake in normal organs and tissues. Radiolabeled 067-213 holds promise as an imaging probe for noninvasive evaluation of CD73 expression levels in patients. Our data encourage further clinical studies to clarify a role for CD73 monitoring in patients receiving CD73-targeted immune therapy.
Highlights
Extracellular adenosine is a known inhibitor of immune function: adenosine-mediated immunosuppression involves direct effects on antitumor effector cells and indirect effects on antigen-presenting cells, immunoregulatory cells such as regulatory T-cells, and myeloid-derived suppressor cells [1,2]
The protein is expressed at high levels in many types of tumors [5,6,7], and CD73 expression levels are correlated with tumor progression and patient survival [8,9,10,11,12]
Quantitative real-time RT-PCR analysis confirmed that CD73 mRNA expression in MIAPaCa-2 cells was 20-hold higher than that in A431: p < 0.01 (Figure 1A)
Summary
Extracellular adenosine is a known inhibitor of immune function: adenosine-mediated immunosuppression involves direct effects on antitumor effector cells and indirect effects on antigen-presenting cells, immunoregulatory cells such as regulatory T-cells, and myeloid-derived suppressor cells [1,2]. In contrast to normal tissues in which adenosine concentration is low, adenosine is present at high concentrations in cancer tissues [3,4] where it suppresses antitumor immune responses [1]. CD73 expression levels in tumors affect the antitumor effects induced by CD73 blockade [18,19], indicating a need to evaluate tumor CD73 expression levels for optimization of CD73-targeted immune therapy. There is a need to noninvasively determine the intratumoral distribution of tumor-infiltrating CD73-expressing cells and quantify their expression levels. Noninvasive imaging can provide information on the expression of therapeutic targets, in cancer tissues and in normal tissues, and it can predict therapeutic responses and toxicities of the targeted therapies [21]. To estimate the risk of radiation-induced toxicity in humans, a dosimetry study was conducted based on the biodistribution of 111In-067-213 in normal rats: the antibody 067-213 cross-reacts with CD73 expressed in rats
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