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Humanized anti-CD44v6 monoclonal antibody labeled with IRDye800CW.


Chopra A.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2013 May 20 [updated 2013 Jun 28].


The CD44 antigen, a member of the cell adhesion molecule family, is known to promote cell migration and survival during cancer metastasis (1). The mouse CD44 gene contains ~20 exons, of which 10 are variants that are alternatively spliced for incorporation into the molecule, a phenomenon that leads to the production of several CD44 variants (CD44v). The different CD44v forms have been reviewed by Ponta et al. (2). The various CD44v molecules are believed to promote cancer metastasis by modulating a variety of cellular processes that are involved in cell migration and localization in the different organs (3). Among the CD44 variants, the one that contains domain 6 of the exons (CD44v6) is specifically implicated in the tumorigenesis and migration of tumor cells during metastasis (4). The CD44v6 antigen is expressed only in a subset of normal epithelial cells, but it is found in most squamous cell carcinomas and some adenocarcinomas; CD44v6 is rarely observed in tumors with a nonepithelial origin (4). CD44v6 was reported to have higher expression than the epidermal growth factor receptor in head and neck squamous cell carcinoma (HNSCC) tumors (5). Investigators have also shown that the CD44v6 antigen is expressed in 64% of breast cancers, and thus it was suggested to be an appropriate marker for the noninvasive imaging of this cancer (6). Because of its high expression in HNSCC, CD44v6 has been targeted with a monoclonal antibody (MAb), designated U36, for the diagnosis of this cancer in humans (7, 8). The biodistribution of 99mTc-labeled U36 was investigated in patients with HNSSC, and it was shown that the labeled MAb can be used with single-photon emission computed tomography (SPECT) to detect all the primary tumors of HNSCC; however, this technique did not visualize the micro-tumors, tumor nodes with necrosis, or tumors containing keratin or fibrin (7). 188Re-Labeled U36 was evaluated in two clinical trials for the treatment of HNSCC, but the 186Re dose was insufficient to kill small tumors or to decimate single cells from this cancer (9). The use of 211At- and 131I-labeled U36 was evaluated and compared for the in vitro treatment of cells derived from HNSCC; the 211At-conjugated MAb was more lethal to the HNSCC cells than the 131I-labeled homolog (10). In addition, the 211At-labeled MAb was shown to stabilize or decrease the volume of HNSCC xenograft tumors in nude mice (11). Investigators labeled the U36 MAb with 124I or 131I and showed that the two tracers can be used with positron emission tomography (for 124I-labeled U36) or SPECT (for 131I-labeled U36) for the detection of xenograft tumors in nude mice (12, 13). In another study, it was shown that SPECT imaging with 186Re-labeled humanized anti-CD44v6 MAb can detect up to 66% of breast cancer lesions (14). Radiolabeled small molecule compounds and MAbs are often used to detect neoplastic tumors, but these tracers are not suitable for use with image-guided surgical resection of small (and usually non-palpable) cancerous lesions of the breast, such as those observed with ductal carcinoma in situ (DCIS) (15). However, near-infrared fluorescent (NIRF) dyes conjugated to cancer-targeting molecules have been used successfully to visualize tumor boundaries during the surgical removal of cancerous tissues (16). The tumors can be visualized easily with the NIRF tracers because these agents infiltrate the tissues (17) and generate a low background in the lesions (18). On the basis of this information, the humanized anti-CD44v6 MAb was conjugated with IRDye800CW (anti-CD44v6-IRDye800CW), and the biodistribution of the NIRF dye-MAb conjugate was investigated in a mouse model of DCIS (15). The conjugate was also evaluated for the NIRF visualization of DCIS tumors in the rodents.

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