Radionuclide selection and model absorbed dose calculations for radiolabeled tumor associated antibodies

Wessels, Barry W.; Rogus, Ronald D.

doi:10.1118/1.595559

Cited by 231 publications

(98 citation statements)

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“…Several clinical trials are assessing the potential utility of RAIT for solid tumor therapy Hird et al, 1993;Juweid et al, 1997;Meredith et al, 1992;Murray et al, 1994). To improve the outcome, one must select an appropriate radionuclide based on the size of the lesion(s) to be treated and an appropriate form of Ab such that the biological decay is matched with the physical decay of the nuclide (Wessels and Rogus, 1984;Wheldon et al, 1991). Since tumor size affects the energyabsorbed fraction, high-energy b-emitters, such as 90 Y, are theoretically more effective in treating tumors .1 cm in diameter, while small tumors and micrometastases are best treated with low-energy b-emitters like 131 I (Howell et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Application of cytokine intervention for improved radio-antibody dose delivery

et al. 1997

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The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibodyinduced myelosuppression and allow either dose escalation of radio-antibody using 131 The potential efficacy of radiolabeled antibodies as a cancer therapeutic is dependent on the maximal tolerated dose (MTD) that can be achieved and on the frequency at which doses can be administered. Two factors influencing both the MTD and the dose frequency are the radionuclide and the form of immunoglobulin used.A variety of radionuclides are under investigation for radioimmunotherapy (RAIT), and several advantages and disadvantages of each have been reviewed (Goldenberg, 1993). The availability of each radionuclide and the physical characteristics vary, each radionuclide decaying at a characteristic rate, with the release of distinct radio-active emissions and with differences in the distance that their particles travel in tissue. The b decay from 131 I travels a relatively short distance (,1 mm), and its maximum energy of decay is only 806 keV. Other b-emitting radionuclides, such as 90 Y and 188 Re, have a higher maximum energy (2,270 and 2,120 keV, respectively) and diffuse their radiation effect over a larger distance within tissues, having maximum path lengths of up to a few millimeters. The objective in selecting a radionuclide for a particular therapeutic application is to maximize the tumor radiation dose while sparing radiation-sensitive tissues from circulating radiolabeled antibody (Ab). The choice of nuclide, therefore, is in part dependent on (i) tumor size, which affects cross-fire and the energy-absorbed fraction, and (ii) binding heterogeneity (Humm, 1986;Howell et al., 1989). Shorter-range emitters are considered appropriate for smaller tumor masses since they maximize local energy deposition. For larger tumor burdens (diameter .1 cm), they would be unable to produce high enough dose levels in certain regions within the tumor that are antigen-negative or where the Ab is unable to penetrate.Selection of the form of immunoglobulin is another variable to be optimized for effective RAIT. Analysis of the pharmacokinetics of intact Ab and its fragments reveals a shorter plasma half-life (t 1/2 ) and less non-specific retention by non-tumor tissue of bivalent and monovalent fragments (Covell et al., 1986). As a result of the faster clearance rate of fragments, the radiation dose to blood is also much lower than that of the intact Ab. Therefore, a higher dose of radiolabeled fragment can be administered to a mouse (e.g., 1,200 µCi 131 I-F[ab8] 2 vs. 275 µCi 131 I-IgG).Unlike external beam irradiation, radiation energy in RAIT is imparted at a low dose rate over several days to weeks to tissues from internally distributed sources. The total radiation dose delivered and the rate of energy deposition in individual tissues are determined by the biodistribution of the administered radionuclide and the physical characteristics of the emitted particles. Among many influential variables, Ab biodistribution is...

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Section: Discussionmentioning

confidence: 99%

Application of cytokine intervention for improved radio-antibody dose delivery

et al. 1997

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“…Specific activity is an important determinant in radioimmunotherapy (33). However, the role of specific activity in determining the relative advantage of cocktails of radiolabeled antibodies relative to single radiolabeled antibodies has not been explored.…”

Section: Discussionmentioning

confidence: 99%

The Advantage of Antibody Cocktails for Targeted Alpha Therapy Depends on Specific Activity

et al. 2014

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Nonuniform dose distributions among disseminated tumor cells can be a significant limiting factor in targeted α therapy. This study examines how cocktails of radiolabeled antibodies can be formulated to overcome this limitation. Methods: Cultured MDA-MB-231 human breast cancer cells were treated with different concentrations of a cocktail of 4 fluorochrome-conjugated monoclonal antibodies. The amount of each antibody bound to each cell was quantified using flow cytometry. A spreadsheet was developed to "arm" the antibodies with any desired radionuclide and specific activity, calculate the absorbed dose to each cell, and perform a Monte Carlo simulation of the surviving fraction of cells after exposure to cocktails of different antibody combinations. Simulations were performed for the α-particle emitters 211 At, 213 Bi, and 225 Ac. Results: Activity delivered to the least labeled cell can be increased by 200%-400% with antibody cocktails, relative to the best-performing single antibody. Specific activity determined whether a cocktail or a single antibody achieved greater cell killing. With certain specific activities, cocktails outperformed single antibodies by a factor of up to 244. There was a profound difference (#16 logs) in the surviving fraction when a uniform antibody distribution was assumed and compared with the experimentally observed nonuniform distribution. Conclusion: These findings suggest that targeted α therapy can be improved with customized radiolabeled antibody cocktails. Depending on the antibody combination and specific activity of the radiolabeled antibodies, cocktails can provide a substantial advantage in tumor cell killing. The methodology used in this analysis provides a foundation for pretreatment prediction of tumor cell survival in the context of personalized cancer therapy.

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“…12,13,[15][16][17]28,29,[31][32][33][34][35][36] Radioimmunodetection with the use radiolabeled mAbs are preferred for tumor as small as 0.5 cm or residual tumors after surgery, which are sometimes missed by other radiological methods, can be imaged with Ab with γ-emitting radionuclide. To label diagnostic radionuclide like.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12] In tumor targeting with antibody conjugated radioisotopes, directly radiolabeled or by the use of a BFCA, [12][13][14] diagnosis and therapy are closely related. We have been interested in the development of new DOTA derived biomolecule conjugate for diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%