Williams Porcal and Maria Fernanda Garcia (MSc), Universidad de LaRepublica, Montevideo, Uruguay, for providing the bifunctional chelator HYNIC for the studies with 99mTc-Rebmab200, Sofia Swedhem at Chalmers Univesity of Technology, Gothenburg, Sweden for help with the Biacore study and Helena Kahu at the University of Gothenburg, Sweden for cell culture and animal handling
Williams Porcal and Maria Fernanda Garcia (MSc), Universidad de LaRepublica, Montevideo, Uruguay, for providing the bifunctional chelator HYNIC for the studies with 99mTc-Rebmab200, Sofia Swedhem at Chalmers Univesity of Technology, Gothenburg, Sweden for help with the Biacore study and Helena Kahu at the University of Gothenburg, Sweden for cell culture and animal handling. Funding Statement This work was supported by the King Gustaf V Jubilee Clinic Cancer Research Foundation in Gothenburg, Sweden and the Swedish Cancer Society (2013-642 and 644), and by CNPq and FINEP, in Brasil. 211At-Rebmab200 was evaluated, as was the power of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were comparable between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and tumor binding. We also exhibited that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in Morusin tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics. Introduction Targeted alpha-particle therapy is usually a treatment modality that has gained interest for the adjuvant treatment Morusin of microscopic disseminated cancer due to the unique properties of alpha particles to deposit high energy at a cellular level. Among the limited set of possible -emitting radionuclides, 211At is one of the most promising candidates. This radionuclide has been investigated in a number of preclinical studies that utilized the free halide [1] and various astatinated tumor-specific carrier vectors [2], the most common of which are monoclonal antibodies directed against a variety of malignancies [3C5]. Promising preclinical results have been obtained; a study on malignant glioma at Duke University (USA) and a study on ovarian carcinoma at the University of Gothenburg (Sweden) have been translated into phase-I studies [6C8]. Ovarian cancer is frequently diagnosed at an advanced stage with pelvic extension and/or intra peritoneal (i.p.) spread i.e. FIGO stage II-IIIc. It is generally diagnosed late and kalinin-140kDa as a consequence with a poor prognosis. Patients generally respond well to standard treatment, with complete clinical remission after cytoreductive surgery followed by 4C6 months of intravenous chemotherapy. However, among patients diagnosed at a late stage, the 5-12 months survival rate is only ~35%, and the 10-12 months survival rate is usually ~25%. Recurrences are primarily intra-abdominal along the peritoneal surface and are initially occult in the form of micrometastases. This scenario favors development of new local treatment strategies such as radioimmunotherapy. MX35 is usually a murine antibody that reacts strongly with an antigen on the surface of ovarian carcinoma cells and tissues [9] that was later shown to be the sodium-dependent phosphate transporter NaPi2b [10]. In Gothenburg, 12 patients in clinical remission after peritoneal recurrence from ovarian cancer were enrolled in a phase-I study of -radioimmunotherapy with MX35 [6]. Astatinated murine MX35 F(ab)2 fragments with different activities were infused intraperitoneally, with favorable distribution and no toxicity. Only a small fraction of the astatinated antibody escaped the peritoneal cavity; most radioactive decay occurred intraperitoneally due to the suitable half-life of 211At, 7.2 hrs, and the slow efflux to the circulation from human peritoneum. Therefore, we did not observe any bone marrow toxicity, while this is dose limiting in murine i.p. therapeutic models [5]. Based on the encouraging results from this phase-I study, a phase-II investigation of the efficacy of this treatment is planned. The phase-I study described above employed the murine F(ab)2 fragment, but murine antibodies may induce a human anti-mouse Morusin antibody (HAMA) response, limiting the possibilities for fractionated treatment [11]. For clinical use a humanized version of the antibody has been generated and named Rebmab200 [12]. Similar to MX35, it has high affinity to its target and strong reactivity with human ovarian carcinomas, plus the ability to kill tumor cells by causing antibody-dependent cell-mediated cytotoxicity (ADCC), a function absent from the murine antibody. The generation of the humanized version of MX35 motivated this study aiming for a preclinical comparison of the humanized version in relation to the previously used murine antibody. The development of simple methods to label peptides and monoclonal antibodies with radiotracers such as technetium (99mTc) has enabled the detection of many malignancies via molecular imaging [13C16]. Overexpression of some epitopes/proteins in several types.