Development and Evaluation of a Novel Method for Preclinical Measurement of Tissue Vascular Volume

Abstract

Identification of clinically predictive models of disposition kinetics for antibody therapeutics is an ongoing pursuit in drug development. To encourage translation of drug candidates from early research to clinical trials, clinical diagnostic agents may be used to characterize antibody disposition in physiologically relevant preclinical models. TechneScan PYP was employed to measure tissue vascular volumes (V(v)) in healthy mice. Two methods of red blood cell (RBC) labeling were compared: a direct in vivo method that is analogous to a clinical blood pool imaging protocol, and an indirect method in which radiolabeled blood was transfused from donor mice into recipient mice. The indirect method gave higher precision in RBC labeling yields, lower V(v) values in most tissues, and lower (99m)Tc uptake in kidneys and bladder by single photon emission computed tomographic (SPECT) imaging relative to the direct method. Furthermore, the relative influence of each method on the calculated area under the first 7 days of the concentration-time curve (AUC(0-7)) of an IgG in nude mice was assessed using a physiologically based pharmacokinetic model. The model was sensitive to the source of V(v) values, whether obtained from the literature or measured by either method, when used to predict experimental AUC(0-7) values for radiolabeled trastuzumab in healthy murine tissues. In summary, a novel indirect method for preclinical determination of V(v) offered higher precision in RBC labeling efficiency and lower renal uptake of (99m)Tc than the direct method. In addition, these observations emphasize the importance of obtaining accurate physiological parameter values for modeling antibody uptake.

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

“…The vascular volumes, interstitial volumes, and rates of blood flow of MC38 and Cloudman tumors were measured in vivo by the indirect method for 99m Tc red blood cell labeling, 30 jugular cannula infusion of 111 In-pentetate, and intravenous bolus injection of 86 Rb chloride, respectively, as previously described. 31 Pharmacokinetic assay for PRO304397…”

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.…”

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

“…Dose-normalized exposures of 111 Inanti-TENB2-MMAE, expressed as area under the concentration-time curve from 0 to 3 days (AUC 0-3 ) values, were 23, 46, 70, and 76 percentage injected dose per milliliter (%ID/ mL) · days with a 0, 1, 3 and 10 mg/kg predose, respectively. For comparison, the analogous AUC 0-3 value for trastuzumab, a typical nonbinding humanized IgG1 with linear pharmacokinetics in mice, is 68 percentage injected dose per gram (%ID/g) · days (23). The rapid clearance of the cross-reactive anti-TENB2-MMAE at low doses reflects its dynamic interac- tion with both human and murine TENB2 in the LuCaP 77 tumor-bearing mouse model, resulting in extensive tissue and tumor uptake.…”

“…We also measured the vascular and interstitial volumes of tumors relative to that of normal tissues to mechanistically understand the differential impact of predosing on uptake in tumors and in tissues not expressing tumor antigen (23,25). No significant difference in vascular volume was determined between the tumor and either small or large intestines (ranging from 8 to 13 mL of blood per gram, or about 1% blood by volume) (Supplemental Table 1; supplemental materials are available online only at http://jnm.snmjournals.org).…”