TY - JOUR
T1 - Radiolabeled antibodies in prostate cancer
T2 - A case study showing the effect of host immunity on antibody bio-distribution
AU - Vilhelmsson-Timmermand, Oskar
AU - Santos, Elmer
AU - Thorek, Daniel L.J.
AU - Evans-Axelsson, Susan
AU - Bjartell, Anders
AU - Lilja, Hans
AU - Larson, Steven M.
AU - Strand, Sven Erik
AU - Tran, Thuy A.
AU - Ulmert, David
N1 - Funding Information:
We wish to thank Anna Åkesson and Susanne Strömblad at the Department of Medical Radiation Physics for technical assistance. DLJT was supported by the Steven Wynn Young Investigator Award, and DU by the David H Koch Young Investigator Award, both of the Prostate Cancer Foundation. In addition, this study was performed with generous support from the Swedish Cancer Society (project no. 11-0624), the Swedish Science Council, Mrs. Berta Kamprad's Foundation, Gunnar Nilsson's Foundation, the ALF Foundation of the Medical Faculty of Lund University and Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Objectives: Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of 111In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models. Methods: In vivo bio-distribution studies of 111In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. Results: The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of 111In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26±3.9 versus 3.5±0.4%IA/g respectively), and concomitantly lower tumor uptake (25±11 versus 52±10%IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to 111In-DTPA-5A10 did not change tumor accumulation significantly. Conclusions: We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of 111In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers, with respect to gaining information on their performance in the translational setting. Investigators utilizing xenograft models need to assess not only radiolabeling strategies, but also the host immunological status.
AB - Objectives: Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of 111In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models. Methods: In vivo bio-distribution studies of 111In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. Results: The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of 111In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26±3.9 versus 3.5±0.4%IA/g respectively), and concomitantly lower tumor uptake (25±11 versus 52±10%IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to 111In-DTPA-5A10 did not change tumor accumulation significantly. Conclusions: We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of 111In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers, with respect to gaining information on their performance in the translational setting. Investigators utilizing xenograft models need to assess not only radiolabeling strategies, but also the host immunological status.
KW - Antibodies
KW - Biodistribution
KW - FPSA-targeting
KW - Host-immunity
KW - Pre-clinical studies
UR - http://www.scopus.com/inward/record.url?scp=84924853675&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2014.12.012
DO - 10.1016/j.nucmedbio.2014.12.012
M3 - Article
C2 - 25577038
AN - SCOPUS:84924853675
SN - 0969-8051
VL - 42
SP - 375
EP - 380
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 4
ER -