Abstract
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) targeted therapy by anti-CTLA-4 monoclonal antibody (mAb) is highly effective in cancer patients. However, it is extremely expensive and potentially produces autoimmune-related adverse effects. Therefore, the development of a method to evaluate CTLA-4 expression prior to CTLA-4-targeted therapy is expected to open doors to evidence-based and cost-efficient medical care and to avoid adverse effects brought about by ineffective therapy. In this study, we aimed to develop a molecular imaging probe for CTLA-4 visualization in tumor. First, we examined CTLA-4 expression in normal colon tissues, cultured CT26 cells, and CT26 tumor tissues from tumor-bearing BALB/c mice and BALB/c nude mice by reverse transcription polymerase chain reaction (RT-PCR) analysis and confirmed whether CTLA-4 is strongly expressed in CT26 tumor tissues. Second, we newly synthesized 64Cu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-anti-mouse CTLA-4 mAb (64Cu-DOTA-anti-CTLA-4 mAb) and evaluated its usefulness in positron emission tomography (PET) and ex-vivo biodistribution analysis in CT26-bearing BALB/c mice. High CTLA-4 expression was confirmed in the CT26 tumor tissues of tumor-bearing BALB/c mice. However, CTLA-4 expression was extremely low in the cultured CT26 cells and the CT26 tumor tissues of tumor-bearing BALB/c nude mice. The results suggested that T cells were responsible for the high CTLA-4 expression. Furthermore, 64Cu-DOTA-anti-CTLA-4 mAb displayed significantly high accumulation in the CT26 tumor, thereby realizing non-invasive CTLA-4 visualization in the tumor. Together, the results indicate that 64Cu-DOTA-anti-CTLA-4 mAb would be useful for the evaluation of CTLA-4 expression in tumor.
Highlights
Cancer is a complex mixture of host and tumor cells
reverse transcription polymerase chain reaction (RT-PCR) was carried out to examine Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expression in CT26 tumor tissues and cultured CT26 cells, and the results were compared to those obtained with normal colon tissues (Fig. 1)
CT26 is a N-nitroso-N-methylurethane-induced, undifferentiated colon carcinoma cell line and recent cancer immunotherapy studies have shown that CTLA-4 blockade reduced CT26 colon tumor size and was effective in CT26 tumor models [27,28]
Summary
Whereas the human body has the ability to produce an anti-tumor immune response, cancers develop multiple strategies to evade the host immune system [1]. Recent research showed that various tumor cells express CTLA-4 [4]. CTLA-4 targeted therapy augments endogenous response to tumor cells, thereby leading to tumor cell death when utilized on its own or with other therapeutic interventions [3]. It is for this reason that CTLA-4 has attracted attention as a target molecule of cancer immunotherapy [5]. Human anti-CTLA-4 monoclonal antibodies (mAbs), ipilimumab and tremelimumab, were developed for the treatment of cancer patients. Pre-clinical and clinical trials of anti-CTLA-4 mAbs have been conducted for the treatment of other cancers, including colon, breast, lung, ovarian, and prostate cancers [3,6]
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