I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma

Abstract Background I-124 codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in patients with hepatocellular carcinoma (HCC). Fourteen patients with HCC underwent baseline imaging with I-124 codrituzumab (~ 185 MBq, 10 mg). Seven of these patients undergoing sorafenib/immunotherapy with 2.5 or 5 mg/kg of cold codrituzumab had repeat imaging, with co-infusion of I-124 codrituzumab, as part of their immunotherapy treatment. Three patients who progressed while on sorafenib/immunotherapy were re-imaged after a 4-week washout period to assess for the presence of antigen. Serial positron emission tomography (PET) imaging and pharmacokinetics were performed following I-124 codrituzumab. An ELISA assay was used to determine “cold” codrituzumab serum pharmacokinetics and compare it to that of I-124 codrituzumab. Correlation of imaging results was performed with IHC. Short-term safety assessment was also evaluated. Results Thirteen patients had tumor localization on baseline I-124 codrituzumab; heterogeneity in tumor uptake was noted. In three patients undergoing repeat imaging while on immunotherapy/sorafenib, evidence of decreased I-124 codrituzumab uptake was noted. All three patients who underwent imaging after progression while on immunotherapy continued to have I-124 codrituzumab tumor uptake. Pharmacokinetics of I-124 codrituzumab was similar to that of other intact IgG. No significant adverse events were observed related to the I-124 codrituzumab. Conclusions I-124 codrituzumab detected tumor localization in most patients with HCC. Pharmacokinetics was similar to that of other intact iodinated humanized IgG. No visible cross-reactivity with normal organs was observed

Additional file 1: of I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma

Table S1. H score by Ventana method for GPC3 expression. Figure S1. SUVs over normal organs and tissues derived from VOI analysis were divided by SUV in the blood pool at various imaging times. With the exception of the thyroid, which showed increasing accumulation over time and therefore rising tumor-to-blood-pool ratios, activity in other organs had fixed organ-to-blood-pool ratios (spleen and lung) or minimally significantly increased in the liver, kidney, and marrow over time (one-way ANOVA p ≤ 0.05, suggesting that accumulation in those organs was accounted for mainly by the blood pool). Figure S2. Correlation between SUVmax in tumor and soluble GPC3 values measured by GT30/GT607 pair (A) or GT96/M3C11 pair (B). There is a suggestion of some correlation of uptake to sGPC3 values. Figure S3. Pearson correlation between SUVmax in tumor compared to IHC score based on cytoplasm (A) or membrane staining (B). There is a trend to correlation of uptake of antibody expressed in terms of SUV to IHC score. Figure S4. No correlation was observed between SUVmax uptake and various clinical outcomes. (DOCX 300 kb

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