Anti-CD45 antibody-drug conjugate(Magenta Therapeutics)

Anti-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.

To 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.

Visual 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).

The presented method can be used to individually determine the optimal preload and the corresponding residence times in radioimmunotherapy with anti-CD45 antibody.