Analysing saturable antibody binding based on serum data and pharmacokinetic modelling.
In radioimmunotherapy, organ dose calculations are frequently based on pretherapeutic biodistribution measurements, assuming equivalence between pretherapeutic and therapeutic biodistribution. However, when saturation of antibody binding sites is important, this assumption might not be justified. Residual antibody and different amounts of administered antibody may lead to a considerably altered therapeutic biodistribution. In this study we developed a method based on serum activity measurements to investigate this effect in radioimmunotherapy with (90)Y-labelled anti-CD66 antibody. Pretherapeutic and therapeutic serum activity data of ten patients with acute leukaemia were fitted to a set of four parsimonious pharmacokinetic models. All models included the key mechanisms of antibody binding, immunoreactivity and degradation; however, they differed with respect to linear or nonlinear binding and global or individual fitting of the model parameters. The empirically most supported model was chosen according to the corrected Akaike information criterion. The nonlinear models were most supported by the data (sum of probabilities approximately 100%). Using the presented method, we identified relevant saturable binding for radioimmunotherapy with (90)Y-labelled anti-CD66 antibody solely based on serum data. This general method may also be applicable to investigate other systems where saturation of binding sites might be important.
Klinik für Nuklearmedizin, Universität Ulm, D-89070 Ulm, Germany. peter.kletting@uniklinik-ulm.de
Peter
P
Kletting
Hady
H
Kiryakos
Sven N
SN
Reske
Gerhard
G
Glatting
D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D008954:Models, Biological; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules