9 research outputs found
ImmunoPET Imaging of Endogenous and Transfected Prolactin Receptor Tumor Xenografts
Antibodies
labeled with positron-emitting isotopes have been used
for tumor detection, predicting which patients may respond to tumor
antigen-directed therapy, and assessing pharmacodynamic effects of
drug interventions. Prolactin receptor (PRLR) is overexpressed in
breast and prostate cancers and is a new target for cancer therapy.
We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET
reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine
B or labeled with I-131/I-124. In vitro determination of the half-maximal
inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878,
and iodinated REGN2878 was performed by examining the effect of the
increasing amounts of these on uptake of trace-labeled I-131 REGN2878.
REGN1932, a non-PRLR binding antibody, was used as a control. Imaging
and biodistribution studies were performed in mice bearing tumor xenografts
with various expression levels of PRLR, including MCF-7, transfected
MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines.
The specificity of uptake in tumors was evaluated by comparing Zr-89
REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878
uptake in tumor xenografts with and without prior injection of 2 mg
of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878
at ratios of 3.53–5.77 DFO per antibody showed IC50 values
of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental
REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution
studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive
xenografts at delayed times of 189 h (presented as mean ± 1 SD,
percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL).
In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0
± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake
and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89
REGN2878 has excellent antigen-specific targeting in various PRLR
tumor xenograft models. We estimated, using image-based kinetic modeling,
that PRLR antigen has a very rapid in vivo turnover half-life of ∼14
min from the cell membrane. Despite relatively modest estimated tumor
PRLR expression numbers, PRLR-expressing cells have shown final retention
of the Zr-89 REGN2878 antibody, with an uptake that appeared to be
related to PRLR expression. This reagent has the potential to be used
in clinical trials targeting PRLR