Modelling radioimmunotherapy with anti-CD45 antibody to obtain a more favourable biodistribution

 

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Summary

Radioimmunotherapy (RIT) is a method to selectively deliver radiation to malignant haemato logical cells by addressing specific antigens. One approach to improve the bio-distribution is to administer a preload of unlabelled antibodies. The aim of this study was to develop a model, which describes distribution of labelled and unlabelled antibodies based on the tissue blood flow and the competing binding behaviour of the antibodies. Such a model can be used to improve biodistribution in the particular case of RIT using anti-CD45 antibodies. Methods: A compartmental model for the interconnected organs was developed. Reaction constants and organ specific flow, antigen concentrations and distribution volumes were taken from the literature. The organ residence times were calculated for different amounts of given labelled and unlabelled antibodies and the time delay between their administrations. Results: The model is capable to describe the preloading effect. The biodistribution of labelled or unlabelled antibodies depends essentially on the specific blood flow to the organ and its antigen expression. The dose ratio of bone marrow to liver is maximized by applying sufficient unlabelled monoclonal antibody (mAb) to saturate antibody binding in the competing organs and by applying the labelled mAb with a delay of more than one hour. Conclusions: The developed model qualitatively describes how a preload can considerably increase selectivity of RIT due to different blood flows and antigen distribution in relevant organs. In addition, simulations can identify the optimal delay between the application of labelled and unlabelled antibody. For future analyses, i.e., to fit patient data, degradation and excretion should be incorporated into the model.

Zusammenfassung

Die Radioimmuntherapie (RIT) erlaubt die selektive Bestrahlung maligner hämatologischer Zellen durch Adressierung spezifischer Antigene. Ein Ansatz zur Verbesserung der Bioverteilung ist die vorherige Gabe von unmarkiertem Antikörper. Ziel war es, ein Modell für die pharmakokinetische Bioverteilung von markierten und unmarkierten monoklonalen anti-CD45-Antikörpern zu entwickeln, um die Abhängigkeit der Biodistribution von den Mengen verabreichter unmarkierter Antikörper und vom Zeitraum zwischen der Verabreichung markierter und unmarkierter Antikörper zu beschreiben. Solch ein Modell kann zur Verbesserung der RIT mit anti-CD45-Antikörpern eingesetzt werden. Methoden: Ein nichtlineares Kompartiment-Modell wurde entwickelt. Die Reaktionskonstanten, organspezifischen Flusskonstanten, Antigenkonzentrationen und Verteilungsvolumina wurden aus der Literatur übernommen. Die Verweildauern wurden in Abhängigkeit von verabreichten markierten und unmarkierten Antikörpern und dem Zeitraum zwischen ihrer Verabreichung untersucht. Ergebnisse: Das Modell kann den so genannten Preload-Effekt beschreiben. Die Biodistribution markierter und unmarkierter Antikörper ist abhängig vom organspezifischen Blutfluss und der Antigenexpression. Das Verhältnis der Verweildauern von Knochenmark und Leber wird bei Verabreichung einer für die Sättigung der konkurrierenden Antikörper-bindenden Organe ausreichenden Menge an unmarkierten Antikörpern und einer um eine Stunde verzögerten Applikation markierter Antikörper optimal. Schlussfolgerungen: Das entwickelte Modell kann qualitativ beschreiben, wie eine vorhergehende Verabreichung unmarkierter Antikörper die Selektivität der Radioimmuntherapie mit anti-CD45-Antikörpern aufgrund der verschiedenen Blutflüsse und Antigenmengen in den akkumulierenden Organen erhöht. Auch der optimale Zeitraum zwischen der Verabreichung kalter und heißer Antikörper ist durch Simulationen bestimmbar. Für weitere Analysen, d. h. um Patientendaten an das Modell anzupassen, müssen noch Abbau und Ausscheidung in das Modell integriert werden.

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