Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.

Goldenberg, David M.; Horowitz, Jo Ann; Sharkey, Robert M.; Hall, Thomas C.; Murthy, Sumathi; Goldenberg, Hildegard; Lee, R E; Stein, Rhona; Siegel, Jeffry A.; Izon, D.

doi:10.1200/jco.1991.9.4.548

Cited by 177 publications

(41 citation statements)

References 41 publications

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“…To a large extent this accumulation resembles the antibody mediated uptake of 9'Yttrium and '3'Iodine in lymphomas in the clinical studies of Vriesendorp et al (1989Vriesendorp et al ( , 1991, Press et al (1989) and Goldenberg et al (1991). In these studies very promising tumour reductive effects were obtained in lymphoma patients.…”

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confidence: 54%

Gallium-67 radiotoxicity in human U937 lymphoma cells

Jonkhoff

Huijgens²,

Versteegh³

et al. 1993

Br J Cancer

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Summary Promising clinical results have been obtained with radiolabeled antibodies in lymphoma patients. The higher uptake by lymphomas of 67Gallium (6'Ga) compared with monoclonal antibodies makes selective radiotherapy by the widely available 67Ga appealing. However, the gamma radiation of 67Ga uised in scintigraphy is considered to be almost non-toxic to lymphoma cells. However, in addition to photon radiation 67Ga emits low energy Auger electrons and 80-90 keV conversion electrons which could be cytotoxic. The objective of the present study was the assessment of radiotoxicity of 67Ga on a lymphoid cell line: U937. Proliferation (MTT-assay) and clonogenic capacity (CFU-assay) were measured after 3 and 6 days incubation with 10, 20 and 40 LCi ml -' 67Ga.Growth inhibition was 36% after 3 days incubation and 63% after 6 days incubation with 40 jICi 67Ga ml-'. Clonogenic capacity was reduced by 51% after 3 days and 72% after 6 days incubation with 40 jiCi ml-67Ga. A survival curve showed an initial shoulder and became steeper beyond 200-250 pCi cell-' (low linear energy transfer type). Iso-effect doses of 67Ga and 9'Yttrium (9Y) were determined. The iso-effect dose of 40 jICi 67Ga ml-' (cumulative dose of conversion electrons 306 cGy) was 2.5 jiCi 90Y ml-' (cumulative dose 494 cGy) and the iso-effect dose of 80 pCi 67Ga ml-was 5.0 pCi 90Y/ml. The main cytotoxic effect of 67Ga seems to be induced by the 80 keV conversion electrons. We conclude that the conversion electrons of 67Ga have a cytotoxic effect on U937 cells and that in our experiments a 16-fold higher piCi-dose of 67Ga than of 9Y was needed for the same cytotoxic effect. We believe that 67Ga holds promise for therapeutic use. 67Gallium (67Ga) In the present study we investigated the cytotoxic effect of 67Ga on a lymphoma cell line: U937. Iso-effect doses of 67Ga and 9Yttrium (90Y) were sought to relate the cytotoxic effect of 67Ga to the well known cytotoxic effect of 'Y. Materials and methodsRadionuclides 67Gallium was obtained from Mallinckrodt Diagnostics Holland B.V. as 67-Ga-chloride. 67Ga-citrate was prepared as follows: 0.1 ml GaC13 (0.7-0.8 N HCI, specific activity: 50 mCi ml -) was added to 4.0 ml Na-citrate stock solution. This stock solution was prepared as follows: 1.17 ml Nacitrate (Trisodium-citrate, C6H5Na307.2H2O), 150 gr-1') was added to 15 ml 0.1 N NaOH and the mixture diluted to 100 ml with NaCl 0.9% and the pH adjusted to 7.0. For sterilisation a micropore filter 0.2 jLm (Schleicher & Schuell) was used.9Yttrium colloidal citrate was obtained from CIS bio international, ORIS industry S.A., Gif-sur-Yvette Cedex, France. Specific activity: 4.3 mCi ml '.For purposes of convenience, activities are given as mCi, jiCi and pCi (1 mCi = 37 MBq).Cells and culture conditions U937 cells, originally derived from a patient with a diffuse histiocytic lymphoma, were purchased from ATCC (Rockville, Maryland, USA), and have been maintained in RPMI-1640-L-Glutamine (Gibco-Europe, Breda, NL) with 10% heat-inactivated foetal calf serum (FCS; Gibco, B...

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confidence: 54%

Gallium-67 radiotoxicity in human U937 lymphoma cells

Jonkhoff

Huijgens²,

Versteegh³

et al. 1993

Br J Cancer

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“…Clinically, RAIT is quite effective in the treatment of lymphoma (Denardo et al, 1988;Goldenberg et al, 1991;Kaminski et al, 1993;Press et al, 1989) and is considered a promising adjuvant for treating occult micrometastatic disease (Blumenthal et al, 1992b). 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).…”

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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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“…The radiosensitivity of lymphoma, as well as the availability of accessible target antigens, has led to the development of several radioimmunoconjugates with therapeutic activity (Press et al, 1989;Goldenberg et al, 1991Goldenberg et al, , 2001Kaminski et al, 1992;Cheson, 2003Cheson, , 2005Press, 2003;Silverman et al, 2004;Theuer et al, 2004;.…”

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Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

Leonard

Goldenberg

2007

Oncogene

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The vast majority of non-Hodgkin's lymphomas are of B-cell phenotype. Development of unlabeled or radiolabeled therapeutic monoclonal antibodies against the cell surface antigen, CD20, has revolutionized the treatment of these malignancies. It is clear that antibodies targeting other B-cell-specific molecules, such as CD22, also offer potential therapeutic benefit. Epratuzumab is a humanized anti-CD22 monoclonal, which has undergone preclinical and phase I/II clinical evaluation in patients with indolent or aggressive lymphoma. Data suggest that this agent is well tolerated, and can induce tumor regressions. Trials are currently evaluating its safety and activity in combination with rituximab (chimeric anti-CD20) and standard chemotherapy are ongoing. Initial results suggest that these regimens have acceptable toxicity, and that epratuzumab warrants further evaluation as an adjunct to standard lymphoma treatment regimens.

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Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.

Cited by 177 publications

References 41 publications

Gallium-67 radiotoxicity in human U937 lymphoma cells

Gallium-67 radiotoxicity in human U937 lymphoma cells

Application of cytokine intervention for improved radio-antibody dose delivery

Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

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