Zr-Labeled fresolimumab (human anti-transforming growth factor-β monoclonal antibody)

The transforming growth factor-β (TGF-β) belongs to a superfamily of cytokines that mediate their activity through serine/threonine kinase receptors and are involved in a variety of cellular processes such as proliferation, differentiation, and migration (1, 2). The TGF-β is a tumor suppressor, but under certain cellular conditions it can promote tumor progression and cancer metastasis as discussed by Meulmeester and ten Dijke (2) and Inman (3). Although TGF-β and its receptors are considered to be important targets for the treatment of highly invasive tumors such as glioblastomas and those of breast cancer, no drug or antibody is available to inhibit the activity of this cytokine or its receptor signaling pathway to treat these malignancies (4). A subset of breast cancer patients exhibited overexpression or suppression of genes related to the TGF-β signaling pathway, and these individuals also showed a shorter metastasis-free or relapse-free survival (5). Therefore, noninvasive imaging of TGF-β will not only help in understanding the functioning of this receptor–ligand system and assist in the development of novel agents that can target the TGF-β or its receptor, but it will also assist in the selection of patients who would benefit most from such an anti-cancer treatment (5). Fresolimumab, a human anti-TGF-β monoclonal antibody (mAb) that neutralizes all active isoforms of TGF-β, was developed and used in a phase I study for the treatment of 22 patients with advanced melanoma and renal cell carcinoma (5). After the treatment, one patient showed stable disease, one patient had a partial response, and three patients showed a mixed response. In addition, no dose-limiting toxicity with the Ab was apparent in the patients. To further improve the likelihood of a positive outcome after the treatment with fresolimumab, it would be helpful to know if the TGF-β or its receptor are overexpressed and activated in the tumor, and also whether the mAb is able to detect such tumors. For this, Oude Munnink et al. evaluated Zr-labeled fresolimumab ([Zr]-fresolimumab) for the detection and quantification of tumors that overexpress TGF-β with positron emission tomography (PET) in a nude mouse model (5). The investigators chose to label the mAb with Zr because it has a long half-life (~78 h), and is also suitable to study binding of the labeled antibody to the tumor and to monitor its organ distribution in animal models. The biodistribution of [Zr]-fresolimumab was also studied in mice bearing xenograft tumors that express varying levels of TGF-β.