Ga-Labeled NOTA-conjugated anti-CD105 (endoglin) chimeric monoclonal antibody

The CD105 antigen (endoglin) is a hypoxia-inducible, 180-kDa, disulfide-linked homodimeric transmembrane glycoprotein that is a co-receptor for the transforming growth factor β (TGF-β) (1). Both CD105 and TGF-β are expressed at low levels in resting endothelial cells, but they are overexpressed in cancerous lesions and play a significantly proangiogenic role in remodeling the vasculature of malignant tumors (2). It has been shown that the levels of CD105 in endothelial tissues correlate well with the degree of cell proliferation, and that the antigen is a suitable biomarker to quantify tumor angiogenesis and can be used to determine the prognostic outcome for cancer patients (3). Investigators have reported that immunotoxins and radioimmunoconjugates generated with anti-CD105 monoclonal antibodies (mAbs) can inhibit angiogenesis and prevent the growth and metastasis of cancerous tumors (4). The biological activity of CD105 has been discussed in detail by Seon et al. (4). For translation to the clinic, a human/mouse chimeric anti-CD105 mAb (designated c-SNj6 or TRC105) has been generated and shown to have suitable pharmacokinetic, toxicological, and immunogenicity characteristics for use in non-human primates (5). Currently, a clinical trial is in progress to evaluate the use of TRC105 for the treatment of metastatic breast cancer. TRC105 has been labeled with Cu (6) and Zr (7), respectively, and shown to detect the expression of CD105 with positron emission tomography (PET) imaging in xenograft tumors in mice. In another study, TRC105 was conjugated to IRDye 800CW, a near-infrared fluorescent (NIRF) dye, and the expression of CD105 in tumors was visualized with NIRF imaging (8). TRC105 has been conjugated with Cu and IRDye 800CW to develop a dual-modality (PET/NIRF) imaging agent that has been used to detect murine breast cancer 4T1 cell tumors in mice (9). Recently it has become possible to produce Ga ( = 9.3 h, = 4.15 MeV), which has a very high specific activity and reacts with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), a bifunctional chelating agent, to yield a product ([Ga]-NOTA) that has a specific activity of >70 GBq/μmol (>2 Ci/μmol), a value that is several-fold higher than those published in the literature (<4.6 GBq/μmol (~125 mCi/μmol)) (10). The investigators suggested that the high specific activity of the NOTA-conjugated radionuclide could be utilized to label peptides and biomolecules such as proteins and mAbs for PET imaging. In an ongoing effort to develop an immuno-PET agent that would be suitable for the noninvasive imaging of angiogenesis in tumor, TRC105 was conjugated with NOTA, labeled with Ga ([Ga]-NOTA-TRC105), and evaluated for the PET visualization of CD105 expression in 4T1 cell tumors in mice (11).