Improved tumor radioimmunodetection using a single-chain Fv and gamma-interferon: potential clinical applications for radioimmunoguided surgery and gamma scanning.
Previous studies have shown that (a) single-chain antibody binding proteins, or sFvs, localize experimental tumor xenografts (D.E. Milenic et al, Cancer Res., 51: 6363-6371, 1991) and (b) the administration of gamma-interferon (IFN-gamma) increases the expression of a high molecular weight glycoprotein, tumor-associated glycoprotein 72 (TAG-72), which improves mAb-based tumor targeting as well as radioimmunotherapy (J. W. Greiner et al., Cancer Res., 53: 600-608, 1993). The present experimental study was designed to determine whether exploiting those two observations in combination could augment tumor detection. Initial results revealed significant localization of a single-chain antibody binding protein of CC49 (i.e., CC49 sFv), a second generation anti-TAG-72 mAb, to human colon tumor xenografts (HT-29), which express low constitutive TAG-72 levels. IFN-gamma treatment of mice bearing HT-29 tumors significantly increased TAG-72 levels in the tumor xenografts. Increased TAG-72 expression was accompanied by a 2-4-fold augmentation of CC49 sFv localized to the HT-29 tumors, measured by direct quantitation of 125I-labeled CC49 sFv tumor deposition as well as tumor:normal tissue ratios. Enhanced CC49 sFv tumor localization improved HT-29 tumor visualization by external scintigraphy as well as when using a hand-held gamma-detecting probe to discriminate between normal (i.e., heart, hind leg) and tumor tissue. The gamma-detecting probe was the same as that used intraoperatively with 125I-labeled CC49 IgG to identify occult tumors in patients. The present experimental findings indicate that the efficiency by which 125I-labeled CC49 sFv localizes tumor in vivo can be enhanced with IFN-gamma. Results of the present study suggest that (a) the incorporation of an IFN-gamma treatment schema prior to radioimmunscintigraphy may increase the signal from the tumor site(s), thus providing a better discrimination between tumor and background, and (b) combining 125I-labeled CC49 sFv with IFN-gamma will not only reduce the time interval between antibody injection and surgery, but will also increase the efficiency of tumor localization using the intraoperative gamma-detecting probe.
Nieroda
C A
CA
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Milenic
D E
DE
Carrasquillo
J A
JA
Scholm
J
J
Greiner
J W
JW
D000818:Animals; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm / Q000032:analysis; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000032:analysis; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging; D005720:Gamma Rays; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging*; D011877:Radionuclide Imaging; D014183:Transplantation, Heterologous
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D006023:Glycoproteins; D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv; C047052:tumor-associated antigen 72; D007371:Interferon-gamma