Red marrow dosimetry for radiolabeled antibodies that bind to marrow, bone, or blood components

Sgouros, George; Stabin, Michael G.; Erdi, Yusuf E.; Akabani, Gamal; Kwok, Cheuk S.; Brill, A. B.; Wessels, Barry W.

doi:10.1118/1.1288393

Cited by 61 publications

(49 citation statements)

References 84 publications

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“…Bone marrow concentrations of blinatumomab following blinatumomab administrations were assumed to be about 30% of that in the plasma based on literature report. 46 The model simulation suggested that following either the priming dose (9 µg/day) or the full dose (28 µg/day), blinatumomab is expected to cause near-complete or complete B cell depletion in blood (Figure 5a). Meanwhile, the model simulation results suggested that blinatumomab would induce incomplete depletion of B cells in bone marrow following the 9 µg/day priming dose, but that blinatumomab will lead to near complete depletion of bone marrow B cells following the 28 µg/day full dose, even at a relatively low baseline E:T ratio (assumed 1: 10 in the current simulation) (Figure 5b).…”

Section: Resultsmentioning

confidence: 99%

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

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Section: Resultsmentioning

confidence: 99%

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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“…For radiopharmaceuticals that bind to marrow tissues or to mineral bone, explicit knowledge of the patient's total and, in some cases, regional active marrow mass is required for proper scaling of radionuclide S values (4), which are in turn assessed in a reference computational phantom or skeletal model (5,6). Under the assumption that no adjustments are required of the radiation-absorbed fraction-fraction of emitted particle energy that is absorbed in the target tissuepatient-specific S values to AM from radiopharmaceuticals localized in skeletal source tissue r S may be estimated as: Eq.…”

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confidence: 99%

Method for Estimating Skeletal Spongiosa Volume and Active Marrow Mass in the Adult Male and Adult Female

Pichardo¹,

Trindade²,

Brindle³

et al. 2007

Journal of Nuclear Medicine

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Active bone marrow is one of the more radiosensitive tissues in the human body and, hence, it is important to predict and possibly avoid myelotoxicity in radionuclide therapies. The MIRD schema currently used to calculate marrow dose generally requires knowledge of the patient's total skeletal active marrow mass-a value that, at present, cannot be directly measured. Conceptually, the active marrow mass in a given skeletal region may be obtained given knowledge of the trabecular spongiosa volume (SV) of the bone site. A recent study has established a multiple regression model to easily calculate total skeletal SV (or TSSV) based on simple skeletal measurements obtained from a pelvic CT scan or radiograph. This model, based on data from only 20 cadavers, did not account for sex differences in TSSV. This study thus extends this work toward sex-specific models. Methods: Twenty male and 20 female cadavers were subjected to whole-body CT. Bone sites containing active bone marrow were manually segmented to obtain SV at each site. In addition to age and height, 14 CT-based skeletal measurements were recorded for each cadaver. Multiple linear regression techniques were used to determine the best subset of measurements that allowed an accurate prediction of TSSV. Results: A pooled model (R 2 5 0.76) and a sex-specific model (R 2 5 0.79) are provided. A leave-one-out analysis reveals that these models predict total SV with less than 10% error for 50%-70% of subjects, and with less than 20% error for 70%-90% of subjects. Tables were constructed that provide the percent distribution of SV in active-marrow containing bone sites for both males and females. Conclusion: This study provides models that can be used to simply, yet accurately, predict total SV in individuals within the clinical setting. The models require only 2 or 3 skeletal measurements that can be easily measured on a pelvic CT scan. Even though this study does not conclusively determine which model is best at predicting TSSV, the sex-specific model is most consistent at providing reasonable estimates of TSSV. This study also explains how the predictive TSSV model can be used to estimate patient-specific active bone marrow mass under the assumption of reference values of marrow volume fraction and bone marrow cellularity by skeletal site.

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“…The use of a scintigraphic method has the advantage of taking the actual activity in the bone marrow into account. 6 The poor correlation between absorbed dose and hematologic toxicity may partly be due to shortcomings of the dosimetry methods in use. Improved knowledge of activity distribution might improve the correlation.…”

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confidence: 99%

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry

Hindorf

Lindén

Tennvall

et al. 2002

Cancer

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BACKGROUND The method for red marrow dosimetry in radioimmunotherapy, in the absence of specific activity uptake in red marrow, is based on the activity measured in the blood or plasma. The activity concentration ratio of red marrow to blood is then assumed to be constant. The aim of the current study was to determine whether this ratio varies with time after injection. METHODS Measurements were carried out with both animals and patients.Tumor‐bearing rats were intravenously injected with iodine‐131–, iodine‐125–, indium‐111–, or rhenium‐188–labeled BR96, a chimeric immunoglobulin G1 monoclonal antibody. (All were chelate‐labeled, except for iodine‐131, which was iodogen‐labeled.) Measurements were made of the activity concentration in blood and bone marrow at different points in time after injection, and the ratio of activity concentration in red marrow and blood as a function of time postinjection (RMBLR[t)]) was calculated. For patients treated with iodine‐131–labeled monoclonal antibody (LL2, Immunomedics Inc., Morris Plains, NJ; anti‐CD22; immunoglobulin G2 isotype of mouse origin), blood samples were drawn and scintillation camera images taken at different times after injection. The red marrow activity concentration in the sacrum was determined by activity quantification from regions of interest. The activity concentration in blood was also measured. The RMBLR(t) was calculated based on these data. RESULTS For both patients and rats, the RMBLR(t) was increased 72 hours after injection. Furthermore, it was found that the use of a constant RMBLR can lead to an over‐ or underestimation of the absorbed dose in bone marrow. CONCLUSIONS These data demonstrate the difficulty in using fixed values of the activity concentration ratio of red marrow to blood for dosimetry. Cancer 2002;94:1235–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10291

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Red marrow dosimetry for radiolabeled antibodies that bind to marrow, bone, or blood components

Cited by 61 publications

References 84 publications

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Method for Estimating Skeletal Spongiosa Volume and Active Marrow Mass in the Adult Male and Adult Female

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry

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