title: Heterogeneity of monoclonal antibody distribution and radiation dose in tumors: a modeling analysis.
abstract: For successful use of monoclonal antibodies and their conjugates for diagnosis and therapy, it is helpful to understand both macroscopic and microscopic aspects of antibody distribution. Antibody distribution in a tumor is simulated by splicing together information on global pharmacokinetics, transport across the capillary wall, diffusive penetration through the tumor interstitial space, and antigen-antibody interaction. One interesting implication of this simulation is a microscopic dosimetry for radioimmunotherapy. The information of microscopic radioconjugate distribution will enable us to calculate absorbed dose in a tumor at the microscopic scale. The first step is to simulate the spatial antibody concentration profile in a tumor as a function of time after intravenous (bolus) injection, using reasonable values for the parameters involved. The second step is to calculate, also as a function of time, the absorbed radiation dose distribution resulting from each concentration profile. Parameter values for IgG pharmacology and a radiation point source function for I-131 are used to explore the effect of affinity on the antibody distribution and consequent absorbed dose in the tumor. The geometry simulated corresponds to a spherical nodule of densely packed tumor cells. Absorbed doses are calculated for radiation from a single nodule and for a cubic lattice of such nodules. This modeling analysis demonstrates that 1) antigen-antibody binding in tumors can retard antibody percolation; 2) high antibody affinity at a given dose tends to decrease antibody percolation and result in a heterogeneous distribution; 3) heterogeneous antibody distribution results in heterogeneous absorbed dose. This is more apparent in the case of radiation from a single nodule or small tumors. PERC and PERC-RAD, the computer program packages developed for these analyses, provide a convenient and flexible way to assess the impact of macroscopic and microscopic parameters on the distribution of immunoconjugates (PERC) and the consequent absorbed radiation dose in tumors (PERC-RAD). This mathematical model and the general principles developed here can be applied as well as to other biological ligands and beta-emitters.
authors.affiliation: Department of Nuclear Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujimori
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D006801:Humans; D007074:Immunoglobulin G / Q000493:pharmacokinetics; D008433:Mathematics; D008962:Models, Theoretical; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D011879:Radiotherapy Dosage
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G