Potential of Optimal Preloading in Anti-CD20 Antibody Radioimmunotherapy: An Investigation Based on Pharmacokinetic Modeling

Abstract

Recently, it has been suggested that the concept of preloading is limited by using a standard amount of unlabeled antibody. To identify the potential of optimal preloading, a pharmacokinetic model that describes the biodistribution of anti-CD20 antibody was developed. Simulations were conducted for different tumor burdens, spleen sizes, and tumor permeabilities. The optimal amount of unlabeled antibody was determined for each scenario. These simulations show that the currently administered standard amount is not optimal. A preload of 150 mg or lower would result in equal or higher tumor uptake in all cases. For tumors with high permeability, the uptake of labeled antibody could be increased by a factor of 8.5 using the considerably reduced optimal preload. The most sensitive parameter for the choice of the optimal amount of unlabeled antibody is the tumor uptake index. The results indicate that a personalized approach for radioimmunotherapy (RIT) with anti-CD20 antibody is required to account for the interpatient variability. The optimal amount of unlabeled antibody, which has to be determined by using a pharmacokinetic model, could substantially improve tumor uptake and thus RIT with anti-CD20 antibody.

Nanobody-Based Targeting of the Macrophage Mannose Receptor for EffectiveIn VivoImaging of Tumor-Associated Macrophages

“…In antibody-based radioimmunotherapy of non-Hodgkin lymphoma, excess amounts of unlabeled anti-CD20 antibody is predosed to patients before injection of 90 Yor 131 I-conjugated anti-CD20 antibody (39), resulting in increased tracer uptake in tumors and reduced uptake in extratumoral organs such as the spleen. However, determining the optimal cold dose for individual patients is not straightforward because the cold antibody can compete with labeled antibody for free antigen sites in the tumor (40,41). The monovalent-labeled-bivalent-cold Nb approach described here seems an attractive alternative, because bivalent Nbs do not efficiently compete for free binding sites in the tumor, while they block extratumoral sites much more efficiently.…”

Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation

“…However, sequestration of these antibodies by non-tumor tissues endogenously expressing the target receptor may decrease antibody bioavailability and tumor-specific binding. This concept is commonly utilized in the field of radioimmunotherapy, in which a “cold” preload dose of unlabeled antibody is used to improve the bioavailability and targeting of subsequently administered radiolabeled antibodies intended to eradicate a malignant target [41–42]. We evaluated the effects of unlabeled cetuximab preloading on the pharmacokinetics and tumor-targeting of systemically injected cetuximab-IRDye800CW in human patients with HNSCC.…”

Differential Effects of Predosing on Tumor and Tissue Uptake of an111In-Labeled Anti-TENB2 Antibody–Drug Conjugate

“…This strategy has been successfully applied in nuclear imaging and radioimmunotherapy (6)(7)(8). Predosing often improves biodistribution into the effect compartment, yielding improved tumor accumulation of radioimmunoconjugates in xenograft models and in the clinic (9)(10)(11). Herein, we pursue a similar predosing strategy to block normal murine tissue uptake of an ADC in a prostate cancer model without compromising tumor uptake.…”