Tc-Labeled anti-receptor for advanced glycation endproducts polyclonal antibody F(ab’) fragments

The Tc-labeled anti-receptor for advanced glycation endproducts (RAGE) polyclonal antibody F(ab’) fragment, abbreviated as Tc-anti-RAGE pF(ab’) or Tc-anti-RAGE F(ab’), is a radiotracer developed by Tekabe et al. for imaging atherosclerotic lesions by targeting highly expressed RAGE (1). RAGE is a 35-kDa transmembrane receptor of the immunoglobulin (Ig) superfamily (1, 2). RAGE has one V domain, two C domains, one transmembrane domain, and one cytoplasmic tail. The V domain consists of two N-glycosylation sites and is responsible for extracellular ligand binding. RAGE exists in three forms: full-length, membrane-bound, and soluble (1-3). The soluble Isoform of the RAGE protein, which lacks the transmembrane and the signalling domain are thought to counteract the detrimental action of the full-length RAGE. Under physiological conditions, RAGE is expressed at low levels in a variety of cells in a regulated manner, but RAGE is highly expressed in a series of age- and diabetes-related chronic inflammatory diseases and cancer (4-7). The advanced glycation endproducts (AGEs) are the major ligands of RAGE. AGEs are a heterogeneous group of peptides and proteins derived from non-enzymatic glycosylation processes (2, 4). Large amounts of AGEs is formed through metabolism and aging, and this establishes a positive feedback cycle under pathological conditions such as diabetes (1, 3, 8). The interaction between AGEs and RAGE affects almost all types of cells and molecules and results in pro-inflammatory gene activation (7, 9). The pathological effects induced by the AGEs/RAGE interaction include increasing vascular permeability, inhibiting vascular dilation, inducing cytokine secretion, enhancing oxidative stress, and modulating cell response to exogenous growth factors. Understanding of the AGEs/RAGE interaction is crucial to develop new treatment regimens for age- and diabetes-related conditions and cancer (3, 9). In the case of atherosclerosis, AGEs are formed at a high level (10). RAGE itself is expressed in nearly all cell types pertinent for the development and progression of atherosclerotic plaque. The AGEs/RAGE interaction leads to diabetic vascular complications and augments atherosclerotic plaque development and progression (7, 8). In a proof-of-concept study of whether the expression level of RAGE could be detected and thus used as a marker of atherosclerosis, Tekabe et al. developed an anti-RAGE polyclonal antibody F(ab’) fragment and demonstrated the feasibility of using Tc-anti-RAGE pF(ab’) for the noninvasive detection of RAGE in the atherosclerotic plaques in apolipoprotein E–null (ApoE) mouse model (1). The major limitation to this study is that polyclonal antibody fragments and planar imaging modality were used (1). Polyclonal antibodies usually have less specificity and higher background signal compared with monoclonal antibodies. Planar imaging systems have a lower spatial resolution than tomographic imaging systems such as single-photon emission computed tomography.