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Prediction of target receptor occupancy for ALX148, a CD47 blocker, using mechanistic PK/RO modeling
Poster Title: Prediction of target receptor occupancy for ALX148, a CD47 blocker, using mechanistic PK/RO modeling
Submitted on 29 Jun 2020
Author(s): Elena Vasileva, Oleg Demin Jr
Affiliations: Lomonosov Moscow State University, Moscow, Russia, InSysBio, Moscow, Russia
This poster was presented at AACR Virtual Annual Meeting II
Poster Views: 293
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Poster Information
Abstract: Background: ALX148 is one of the anti-CD47 antibodies that are currently in clinical development. Understanding the target receptor occupancy (RO) in tumor can help with dose selection for ALX148 and other anti-CD47 antibodies. However, RO can be challenging to determine through direct experimental measurements. A mechanistic PK/RO model was developed to predict CD47 occupancy in tumor tissues and periphery for ALX148 based on its properties (PK, structure, and affinity).
Methods: Developed mechanistic PK/RO model describes PK of ALX148 in blood plasma, distribution to tumor tissues of Non-Hodgkin lymphoma (lymph nodes, spleen), non-linear clearance of ALX148 due to the binding with CD47 and further complex internalization. RO was described on red blood cells and tumor cells. The model takes into account CD47 expression (molecules per cell) and a number of cells expressing CD47. Parameters were fitted against clinical PK data. Clinical data on RO in the periphery was used for model validation.
Results: The model successfully described ALX148 clinical data on PK and RO in blood plasma. Concentrations in lymph nodes and spleen were predicted to be similar and in approximately 3 times lower than in blood plasma. Such high concentration in tumor tissues is caused by small size of ALX148 (molecular weight is 78 kDa). Dose and regimen chosen for combination treatment (10 mg/kg QW) result in 90-95% trough steady-state RO in tumor tissues. The model predicted that trough steady-state RO in lymph nodes and spleen was more than 95% after administration of maximal dose 30 mg/kg Q2W.
Conclusions: A mechanistic PK/RO model was built to capture ALX148 clinical PK data and then predicted more than 90% RO at the dose used in combination treatment cohort. This approach has the potential to be used to inform dose selection for other anti-CD47 antibodies taking into account their specific features as binding properties, size, etc.
Summary: Developed model successfully described clinical PK & CD47 RO ALX148 data.
Model predicted 30 mg/kg QoW is best regimen among tested in phase I trial.
This model can be applied to the other anti-CD47 biotherapeutic agents.
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