Tumor pretargeting: role of avidin/streptavidin on monoclonal antibody internalization (original) (raw)
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1994
The techniques of radioimmunoimaging and radioimmunotherapy suffer from prolonged high background radioactivity because intravenously injected antibodies remain in the circulation and in the organs far longer than necessary for effective binding to the target. To decrease background and increase radionuclide excretion without decreasing the dose of radioactivity delivered to the target tumor, we used radiolabeled biotinylated antibodies followed by a "chase" avidin injection. A mouse monoclonal antibody, OST7 (IgG1), which reacts with human osteosarcoma, was biotinylated and labeled with 125I, 131I or 99mTc. Radiolabeled biotinylated OST7 (10 micrograms) was administered intravenously into nude mice bearing human osteosarcomas and 30 micrograms of avidin was injected intravenously 6 or 24 hr later. Following avidin injection in mice pretreated with radiolabeled biotinylated antibodies, radioactivity was promptly cleared from the blood and deposited in the liver and spleen,...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1996
Due to their high affinity for biotin, avidin (Av) and streptavidin (SAv) are used to bridge pretargeted antibody molecules and radiolabeled biotin derivatives in vivo. We compared uptake of 125I-labeled Av or SAv (approximately 10-500 micrograms) in tumor and normal tissues 3 days after a biotinylated B72.3 monoclonal antibody (100 micrograms) injection in nude mice. The animals were killed 24 hr later and the biodistribution of 125I was determined. The percent injected dose per gram of tumor remained constant over the range of injected doses for Av while that for SAv varied. As larger amounts of Av/SAv were injected, the number of moles of each trapped within tumor increased, with the values for SAv being much higher. While the injection of larger doses of Av led to an increase in tumor-to-normal tissue ratios, that of SAv did not. SAv (2.5 mg/kg) is the preferred "second-step" reagent. At this dose, the number of receptors available for targeting by radiolabeled biotin ...
Monoclonal Antibody and Avidin or Streptavidin
1996
Due to their high affinityfor biotin, avidin (Av) and streptavidin (SAy) are used to bridge pretargeted antibody molecules and radiolabeled biotin derivatives in vivo. Methods: We compared uptake of 125l@ labeled AyorSAv (— 1O-500 p@ g) intumorand normal tissues 3 days after a biotinylated B72. 3 monoclonal antibody (100@ &g) injection in nude mice. The animals were killed24 hrlater and the biodistribution of 125lwas determined. Results: The percent injected dose per gram of tumor remaIned constant over the range of injected ...
International Journal of Cancer, 1988
Several monoclonal antibodies (MAbs), reactive with tumor-associated antigens, selectively persist on tumor sites in vivo for many days. If biotinylated, such highly specific tags on tumor cells could become targets for radioactive avidin, administered after suitable intervals. The proposed strategy is based on a number of assumptions concerning the ability of avidin t o preserve i t s biological properties in heterologous in vivo environments, on i t s lack of toxicity and on i t s biodistribution. A preliminary study has been carried out in rabbits, using biotinylated nitrocellulose and polystyrene targets. The results of this study indicate that in rabbits I ) avidin can be administered i.v. and i.p. without adverse reactions, 2) it does not show any preferential localization, 3) it is eliminated with a biological half-life of 24 hr, 4) i t s biological properties are not impaired by in vivo conditions, since it accumulates at biotinylated targets only, 5) CEA-bearing targets can be biotinylated in vivo by biotin-labelled anti-CEA MAbs and 6) the biotin-avidin chain can be further extended in vivo since bound avidin is still able t o bind biotinylated radioactive proteins.
Cancer research, 1994
Two-step monoclonal antibody tumor targeting using an avidin-biotin system has unique characteristics because of the high-affinity binding (10(15) M-1) and the lower molecular weight ligands (avidin, streptavidin, or biotin) used as carriers of radioisotopes, toxins, or drugs. The distribution of radiolabeled streptavidin in a two-step targeting strategy was investigated in lung metastases of line 10 carcinoma in guinea pigs. The microdistribution of administered D3 monoclonal antibody and 125I-labeled streptavidin in metastatic nodules was examined by immunohistochemistry and autoradiography, and the uptake was quantitated. With monoclonal antibody pretargeting, streptavidin was found mainly at the periphery of metastatic nodules 1.5 h after injection; it had penetrated deeper at 4 h and was approaching homogeneity in many of the tumor nodules at 24 h. These results indicate that streptavidin can penetrate into metastatic nodules more rapidly than can the antibody. The concentratio...
Tumor cell targeting with antibody-avidin complexes and biotinylated tumor necrosis factor alpha
Cancer research, 1997
Tumor pretargeting with biotinylated antibodies and avidin, followed by a delayed delivery of radioactive-labeled biotin, is currently used for in vivo diagnosis and therapy in cancer patients. Herein, we describe the use of a three-step antibody/avidin targeting approach to increase the local concentration and the persistence of biotinylated human tumor necrosis factor alpha (bio-TNF) on a mouse tumor. Mouse RMA lymphoma cells were transfected with the Thy 1.1 allele (RMA-Thy 1.1) to generate a unique tumor-associated antigen. In vitro pretargeting of RMA-Thy 1.1 cells with the biotinylated anti-Thy 1.1 monoclonal antibody 19E12 (bio-19E12) and NeutrAvidin increased the amount of bio-TNF that bound to the cell (10-20 times in comparison with non-pretargeted cells), as well as its half-life on the surface (>30 times). Furthermore, cell pretargeting reduced by more than 2 orders of magnitude the LD50 of bio-TNF in a cytolytic assay with actinomycin D. Finally, RMA-Thy 1.1 cells, p...
Tumor cell targeting with antibody-avidin complexes and biotinylated tumor necrosis factor α
1997
Tumor pretargeting with biotinylated antibodies and avidin, followed by a delayed delivery of radioactive-labeled biotin, is currently used for in vivo diagnosis and therapy in cancer patients. Herein, we describe the use of a three-step antibody/avidin targeting approach to increase the local concentration and the persistence of biotinylated human tumor necrosis factor a (bio-TNF) on a mouse tumor. Mouse RMA lymphoma cells were transfected with the Thy 1.1 allele (RMA.Thy 1.1) to generate a unique tumor-associated antigen. In vitro pretargeting of RMA-Thy 1.1 cells with the biotinylated anti-Thy 1.1 monoclonal antibody 19E12 (blo-19E12) and NeutrAvidin Increased the amount of bio-TNF that bound to the cell (10-20 times in comparison with non-pretargeted cells), as well as its half.life on the surface (>30 times). Furthermore, cell pretargeting re duced by more than 2 orders of magnitude the LD@,of bio-TNF in a cytolytic assay with actinomycin D. Finally, RMA.Thy 1.1 cells, pretreated in vilro with blo-TNF according to the three-step procedure and injected
Cancer Biotherapy & Radiopharmaceuticals, 2011
Purpose: Avidin-coupled monoclonal antibody MX35 (avidin-MX35) and astatine-211-labeled, biotinylated, succinylated poly-l-lysine ( 211 At-B-PL suc ) were administered in mice to assess potential efficacy as an intraperitoneal (i.p.) therapy for microscopic tumors. We aimed to establish a timeline for pretargeted radioimmunotherapy using these substances, and estimate the maximum tolerable activity. Methods: 125 I-avidin-MX35 and 211 At-B-PL suc were administered i.p. in nude mice. Tissue distributions were studied at various time points and mean absorbed doses were estimated from organ uptake of 211 At-B-PL suc . Studies of myelotoxicity were performed after administration of different activities of 211 At-B-PL suc . Results: We observed low blood content of both 125 I-avidin-MX35 and 211 At-B-PL suc , indicating fast clearance. After sodium perchlorate blocking, the highest 211 At uptake was found in kidneys. Red bone marrow (RBM) accumulated some 211 At activity. Mean absorbed doses of special interest were 2.3 Gy/MBq for kidneys, 0.4 Gy/ MBq for blood, and 0.9 Gy/MBq for RBM. An absorbed dose of 0.9 Gy to the RBM was found to be safe. These values suggested that RBM would be the key dose-limiting organ in the proposed pretargeting scheme, and that blood data alone was not sufficient for predicting its absorbed dose. Conclusions: To attain a favorable distribution of activity and avoid major toxicities, at least 1.0 MBq of 211 At-B-PL suc can be administered 24 hours after an i.p. injection of avidin-MX35. These results provide a basis for future i.p. therapy studies in mice of microscopic ovarian cancer.