PURPOSEAnti-CD45 antibody is predominantly used in the treatment of acute leukemia. CD45 is stably expressed on all leukocytes and their precursors, and therefore the liver and spleen constitute major antigen sinks. Thus, as the red marrow is the target organ, in radioimmunotherapy with anti-CD45 antibody, preloading with unlabeled antibody is a method to increase the absorbed dose to the target cells. In a previous study, a method to individually determine the optimal preload for five patients with acute leukemia was developed. Here, this method is examined and improved using two pretherapeutic measurement series and a refined pharmacokinetic model.METHODSTo obtain the biodistribution of 111In-labeled anti-CD45 antibody under different saturation conditions, two measurement series one with and one without preloading were conducted in five patients. For each patient, two physiologically based pharmacokinetic models were fitted to the data and the corrected Akaike information criterion was used to identify the model, which was empirically most supported. The resultant parameter values were compared to values reported in the literature. To individually determine the optimal amount of unlabeled antibody for therapy, computer simulations for preloads ranging from 0 to 60 mg were performed based on the estimated parameters of each patient. The prediction power of the model was assessed by comparing the simulated therapeutic serum curves to the actual 90Y measurements.RESULTSVisual inspection showed good fits and the adjusted R2 was >0.90 for all patients. All parameters were in a physiologically reasonable range. The relative deviation of the predicted area under the therapeutic serum curve and the measured curve was 15%-33%. The optimal preloading increased the marrow-over-liver selectivity up to 3.9 fold compared to the simulated biodistribution using a standard dose (0.5 mg/kg).CONCLUSIONSThe presented method can be used to individually determine the optimal preload and the corresponding residence times in radioimmunotherapy with anti-CD45 antibody.

01 Dec 2009·Best Practice & Research Clinical HaematologyQ4 · MEDICINE

Optimising the conditioning regimen for acute myeloid leukaemia

Q4 · MEDICINE

Review

Author: Frederick R. Appelbaum

The conditioning regimen administered prior to allogeneic transplantation for acute myeloid leukaemia (AML) must be sufficiently immunosuppressive to ensure engraftment, and contributes to the anti-leukaemic impact of the procedure. A broad spectrum of regimens have been studied, varying in their intensity, whether high-dose or reduced intensity, and in the agents used, containing total body irradiation (TBI) plus cyclophosphamide, fludarabine, busulfan and/or anti-thymocyte globulin. Over the past 2 decades, research has influenced the way conditioning regimens are applied. Newer research shows that targeted radiotherapy using an anti-CD45 antibody should be able to reduce toxicity, improve tumour cell kill and thereby improve results.

01 Feb 2009·Journal of Nuclear MedicineQ1 · MEDICINE

Improving Anti-CD45 Antibody Radioimmunotherapy Using a Physiologically Based Pharmacokinetic Model

Q1 · MEDICINE

Article

Author: Reske, Sven N ; Glatting, Gerhard ; Kletting, Peter ; Bunjes, Donald

Radioimmunotherapy is a method to selectively deliver radioactivity to cancer cells via specific antibodies. A strategy to enhance the efficacy of radioimmunotherapy is the prior application of unlabeled antibody, resulting in an increase in the dose to the target tissue and a decrease in the burden to other organs. It was suggested that optimizing this approach might considerably improve radioimmunotherapy with anti-CD45 antibody. The present work develops a physiologically based pharmacokinetic model to individually determine the optimal preload for radioimmunotherapy with the YAML568 anti-CD45 antibody for each patient.METHODSA physiologically based pharmacokinetic model was developed to describe the biodistribution of anti-CD45 antibody. The transport of antibody to the organs of interest via blood flow, competitive binding of unlabeled and labeled antibody, degradation and excretion of antibody, and physical decay were included in the model. The model was fitted to the biokinetics data of 5 patients with acute myeloid leukemia. On the basis of the estimated parameters, simulations for a 0- to 534-nmol preload of unlabeled antibody were conducted and the organ residence times were calculated.RESULTSThe measured data could be adequately described by the constructed model. The estimated numbers of accessible antigens in the respective organ, in nanomoles, were 97+/-33 for red marrow, 49+/-24 for liver, 34+/-18 for spleen, 38+/-31 for lymph nodes, and 0.9+/-0.4 for blood. These ranges indicate high interpatient variability. The optimal amount of unlabeled antibody identified by simulations would improve the ratio of residence time in red marrow to residence time in liver by a factor of 1.6-2.4.CONCLUSIONThe efficacy of radioimmunotherapy using anti-CD45 antibody can be considerably increased with the presented model. A more selective delivery of radioactivity to the target organ and a reduction in the toxicity to normal tissue are achieved by determining the optimal preload. Furthermore, the adverse effects of radioimmunotherapy might be drastically reduced while saving antibody expenses. The validation of the model is ongoing. The model is easily extendible and therefore most probably applicable to radioimmunotherapy of other hematologic malignancies, such as antibodies targeted to CD20, CD33, or CD66.

100 Deals associated with Anti-CD45 antibody-drug conjugate(Magenta Therapeutics)

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	US	Magenta Therapeutics, Inc.	-
Arteriosclerosis	Preclinical	US	Magenta Therapeutics, Inc.	-
Autoimmune Diseases	Preclinical	US	Magenta Therapeutics, Inc.	-
Bone marrow transplant rejection	Preclinical	US	Magenta Therapeutics, Inc.	-

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