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Radioiodinated anti–TAG-72 non-covalently linked CC49 divalent single-chain Fv antibody.

Authors

Cheng KT.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2007 Dec 05 [updated 2008 Jan 07].

Excerpt

Radioiodinated anti–TAG-72 non-covalently linked CC49 divalent single-chain Fv antibody (125I/131I-CC49 (scFv)2 Ab), which is formed by the conjugation of 125I/131I with a bioengineered recombinant anti–tumor-associated glycoprotein 72 (TAG-72) antibody construct, has been developed for gamma imaging of cancers that express TAG-72 (1-4). 125I has a physical half-life (t½) of 60 days with a gamma energy that is not ideal for in vivo imaging. 131I has a physical half-life (t½) of 8.02 days with a gamma energy that is high but acceptable for in vivo imaging. The TAG-72 antigen was isolated from the LS-174T human colon cancer xenograft as a high molecular weight glycoprotein (molecular mass of 106 Da) with mucin-like characteristics (5-8). It is expressed on a variety of human adenocarcinomas such as pancreatic, breast, colorectal, prostate, endometrial, and ovarian cancers. This antigen has also been shown to be shed into the serum of cancer patients (9). The murine monoclonal antibody B72.3 (MAb B72.3) against TAG-72 mucin was initially generated by immunization of mice with a membrane-enriched fraction of a human breast carcinoma (10). With the use of affinity-purified TAG-72 from LS-174T as an immunogen, CC49 and other anti–TAG-72 MAbs with higher affinity constants (Ka) have been produced and characterized (5, 6, 10, 11). CC49 MAb appears to react with a unique disaccharide sialyl-Tn (STn) epitope on TAG-72 (2, 4). Radiolabeled MAbs have been developed for both the diagnosis and treatment of tumors (12). Radiolabeled B72.3 and CC49 exhibit excellent tumor localization capabilities with potential diagnostic and therapeutic applications in the clinical setting (13, 14). Because of their relatively large size, intact radiolabeled MAbs tend to have unfavorable imaging kinetics, poor tumor penetration, and high potential for human anti-mouse antibody response (11, 15-17). One approach to minimize these problems is reducing intact antibodies to antibody fragments such as F(ab’)2 and Fab’ (18). Another approach is the development of genetic engineering methods to obtain single-chain Fv constructs (scFv) and multivalent scFv constructs (11, 19, 20). These scFv constructs contain the variable regions of the light chain (VL) and heavy chain (VH) connected by a flexible linker. Colcher et al. (21) constructed the monomeric CC49 scFv Ab (~27 kDa), which selectively recognizes a unique STn epitope of TAG-72. The radioiodinated CC49 scFv appeared to clear rapidly from the blood with good tumor penetration (1, 20). To further improve the imaging kinetics by use of multivalency as a means of increasing the functional affinity, a non-covalently linked dimeric scFv was isolated on the basis of the spontaneous formation of the dimer from the monomeric CC49 scFv (1, 2, 4). This dimeric scFv was designated (scFv)2 to distinguish it from the covalently-linked dimer sc(Fv)2, in which two repeating chains of VL and VH are covalently linked in tandem (4). The radioiodinated CC49 (scFv)2 showed good stability and improved in vivo pharmacokinetics compared with the intact CC49 IgG.

PMID:
20641456
[PubMed]
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