Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

Abstract

BackgroundThe identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences.Methodology/Principal FindingsTechnescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice.Conclusions/SignificanceThese observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.

Pharmacokinetic mAb–mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts

“…For example, it is possible that anti-VEGF treatment alters CEA expression or shedding, which was not measured in this study. The lack of effect of anti-VEGF on T84.66 exposure in non-tumor tissues is consistent with prior demonstrations that anti-VEGF therapy does not affect the vasculature of non-tumor tissues (36).…”

Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model

“…Tissues collected consisted of heart, right kidney, lungs, spleen, muscle (gastrocnemius), normal mammary fat pad, and tumor. Tissue handling and analysis provided counts per minute values, which were used to calculate the percent of injected dose per gram of tissue (%ID/g) and area under the curve (AUC) as previously described (39)(40)(41). Note that %ID/g is a dose-normalized unit of concentration.…”

“…In vivo distribution was obtained by single-photon emission computed tomography/X-ray computed tomography (SPECT-CT) using modification of previously reported methods (39,40). Mice (n ¼ 1) received an average dose of 405 mCi (range: 383-416 mCi) of 111 In-trastuzumab with or without anti-VEGF pretreatment as described above.…”

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

“…These images are informative but cannot show the spatial distribution of cetuximab relative to individual tumor cells and the capillaries supplying them. However, high-resolution spatial and compartmental information about antibody and antigen can be necessary to understanding the interplay of affinity, delivery, and efficacy (33)(34)(35)(36). In the case of anti- IRDye800CW and 100 μCi of Zr-89.…”