Comparative biodistribution analysis across four different Zr-monoclonal antibody tracers-The first step towards an imaging warehouse

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89Zr-lumretuzumab, 89Zr-MMOT0530A, 89Zr-bevacizumab and 89Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions

Phylogeography of Harbour Porpoise (Phocoena phocoena) in the Eastern North Atlantic and in the Black Sea Explored by the Analyses of Nuclear and Mitochondrial DNA

Study of the genetic population structure and the demographic history of the harbour porpoise (Phocoena phocoena) has been nearly comprehensive throughout its distribution in North Atlantic, most studies using the mitochondrial control region as a genetic marker. Although these studies have shown population structure in some parts of the North Atlantic, mitochondrial DNA is a single, maternally inherited locus and therefore insufficient to fully characterize population structure and history. Polymorphism at 11 microsatellite loci was analyzed in harbour porpoises collected throughout the range of the species in the Central and Eastern North Atlantic from the Iberian peninsula northward to Arctic waters (Portugal, Spain, bay of Biscay, Irish waters, English Channel, the southern bay of the North Sea, Norway, Faroe Islands, and Iceland) and also along the coasts of the Black Sea (Turkey, Ukraine, Bulgaria and Georgia). Multilocus tests for allele frequency differences and population structure estimates indicate complete genetic isolation between Atlantic and Black Sea porpoises. No fine population structure was observed within the Black Sea, and this population displayed a low genetic diversity compared to those of Atlantic. These results can be interpreted in the light of the demographic history of this relict population and the strong founder effect and bottleneck it may have undergone in its past evolution. In Eastern North Atlantic waters, microsatellite data revealed fine scale partitioning of the genetic variation. These results will be compared to the pattern previously reported based on the analysis of the mtDNA control region, and seem to correlate with variation in oceanographic features

Zr-89-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Purpose: We evaluated biodistribution and tumor targeting of Zr-89-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)targeting monoclonal antibody. Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received Zr-89-lumretuzumab and underwent positron emission tomography (PET). In part A, (89)-Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV). Results: Optimal PET conditions were found to be 4 and 7 days after administration of Zr-89-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4(+/- 1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (+/- 8.2), 10.0% (+/- 16.5), and 24.6% (+/- 20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab. Conclusions: PET imaging showed biodistribution and tumor-specific Zr-89-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased Zr-89-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. (C) 2017 AACR