Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors

BACKGROUND:Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.METHODS:Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.RESULTS:Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.CONCLUSIONS:Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells

International Pellet Watch: global monitoring of persistent organic pollutants (POPs) in coastal waters. 1. Initial phase data on PCBs, DDTs, and HCHs

Samples of polyethylene pellets were collected at 30 beaches from 17 countries and analyzed for organochlorine compounds. PCB concentrations in the pellets were highest on US coasts, followed by western Europe and Japan, and were lower in tropical Asia, southern Africa and Australia. This spatial pattern reflected regional differences in the usage of PCBs and was positively correlated with data from Mussel Watch, another monitoring approach. DDTs showed high concentrations on the US west coast and in Vietnam. In Vietnam, DDT was predominant over its metabolites (DDE and DDD), suggesting the principal source may be current usage of the pesticide for malaria control. High concentrations of pesticide HCHs were detected in the pellets from southern Africa, suggesting current usage of the pesticides in southern Africa. This study demonstrates the utility and feasibility of the International Pellet Watch approach to monitor POPs at a global scale

International pellet watch: global monitoring of persistent organic pollutants(POPs) in coastal waters. 1. Initial phase data on PCBs, DDTs, and HCHs

Samples of polyethylene pellets were collected at 30 beaches from 17 countries and analyzed for organochlorine compounds. PCB concentrations in the pellets were highest on US coasts, followed by western Europe and Japan, and were lower in tropical Asia, southern Africa and Australia. This spatial pattern reflected regional differences in the usage of PCBs and was positively correlated with data from Mussel Watch, another monitoring approach. DDTs showed high concentrations on the US west coast and in Vietnam. In Vietnam, DDT was predominant over its metabolites (DDE and DDD), suggesting the principal source may be current usage of the pesticide for malaria control. High concentrations of pesticide HCHs were detected in the pellets from southern Africa, suggesting current usage of the pesticides in southern Africa. This study demonstrates the utility and feasibility of the International Pellet Watch approach to monitor POPs at a global scale

Phylogeography of the Japanese white-toothed shrew (Eulipotyphla:Soricidae): a clear division of haplogroups between eastern and western Japan and their recent introduction to some regions

The Japanese white-toothed shrew (Crocidura dsinezumi) is a species endemic to Japan. For this species, only minimal phylogeographic investigations have been conducted. We obtained DNA sequences of mitochondrial cytochrome b and control region and nuclear ApoB genes for 191 individuals of C. dsinezumi from 107 locations collected throughout its known range. In the phylogenetic trees based on mitochondrial DNA sequences, two haplogroups (Eastern and Western Clades) were recognized, and the demarcation line between them was located in central Honshu without an overlapping area. The estimated divergence time between the two major clades indicated that they could have diverged prior to the final geologic division of Hondo and the Asian Continent (100–150 KYA). For the ApoB gene, Types A, G, and R (heterozygote) were recognized although there was a single site mutation. Type A mainly occurs in eastern and central Japan and Types G and R in central and western Japan. It was suggested in the present study that some shrews in Hokkaido were introduced recently from eastern Honshu (possibly the Tohoku Region) whereas others might have been distributed there naturally, and that population in Jeju (South Korea) was introduced recently from Kyushu