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.

Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer

“…2A). This encouraged us to investigate a recently developed hK2-targeting antibody (hu11B6) in AR-positive breast cancer in conjunction with steroid hormone induction of KLK2 (21, 34). We tested the most potent therapeutic variant of this agent; hu11B6 labeled with the cytotoxic a particle emitting radionuclide, [ 225 Ac]hu11B6.…”

PSMA Expression in the Hi-Myc Model; Extended Utility of a Representative Model of Prostate Adenocarcinoma for Biological Insight and as a Drug Discovery Tool

“…There are many agents under development for improved detection and targeted therapy of prostate adenocarcinoma [15][16][17][18][19] . The widespread use of high-sensitivity and robust methods to detect PSMA in particular in the locally advanced and metastatic settings by PET and SPECT are poised to revolutionize management for those afflicted with the disease.…”

In vivo immuno-targeting of an extracellular epitope of membrane bound preferentially expressed antigen in melanoma (PRAME)

“…Whether this specific binding is caused by splenic migration of tumor cells or by cross-reactivity to an epitope similar to PRAME was not confirmed in this study. Splenic uptake could also be related to host immunity [ 26 ]; significant uptake was only noted in murine NSG SCID based liquid tumor models, as opposed to solid. Also, the use of a polyclonal antibody increases the risk of cross-reactivity, and binding to healthy splenic cells will be monitored carefully while selecting a lead monoclonal antibody candidate for clinical translation.…”