Radiolabeled antibodies in prostate cancer: A case study showing the effect of host immunity on antibody bio-distribution Journal Article


Authors: Vilhelmsson-Timmermand, O.; Santos, E.; Thorek, D. L. J.; Evans-Axelsson, S.; Bjartell, A.; Lilja, H.; Larson, S. M.; Strand, S. E.; Tran, T. A.; Ulmert, D.
Article Title: Radiolabeled antibodies in prostate cancer: A case study showing the effect of host immunity on antibody bio-distribution
Abstract: 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. © 2014 Elsevier Inc.
Keywords: controlled study; unclassified drug; nonhuman; comparative study; t lymphocyte; prostate specific antigen; animal cell; mouse; animal tissue; animal experiment; animal model; protein binding; in vivo study; in vitro study; b lymphocyte; prostate cancer; liver; drug accumulation; drug distribution; drug uptake; isotope labeling; radiopharmaceutical agent; natural killer cell; fc receptor; salivary gland; immunity; antibodies; immunoglobulin g1; immune deficiency; gastrointestinal tract; testis; drug stability; case study; biodistribution; parameters; antibody labeling; brain tissue; bone tissue; monoclonal antibody 5a10; male; article; fpsa-targeting; host-immunity; pre-clinical studies; monoclonal antibody 5a10 pentetate indium in 111; liver to blood ratio
Journal Title: Nuclear Medicine and Biology
Volume: 42
Issue: 4
ISSN: 0969-8051
Publisher: Elsevier Science Inc.  
Date Published: 2015-04-01
Start Page: 375
End Page: 380
Language: English
DOI: 10.1016/j.nucmedbio.2014.12.012
PROVIDER: scopus
PUBMED: 25577038
PMCID: PMC4472383
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Hans Gosta Lilja
    345 Lilja
  2. Elmer B Santos
    25 Santos
  3. Hans David Staffan Ulmert
    52 Ulmert
  4. Steven M Larson
    959 Larson