An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the high- and low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML.

Factors that distinguish serious versus less severe strain and sprain injuries: an analysis of electric utility workers.

BACKGROUND: Occupational sprain and strain injuries are one of the most common types of nonfatal occupational injuries and a significant source of lost workdays. This study examines factors associated with severe work-related sprain/strain injuries to the back, shoulder, and knees. METHODS: A synthetic case-control study was performed (controls were selected from the same pool of utility workers as cases). Cases included all electric utility workers who had experienced a severe work-related sprain/strain injury to the back, knee, or shoulder. Primary controls were selected from all workers who had sustained a minor injury. Secondary controls were selected from employees with a minor sprain/strain injury to the back, knee, or shoulder. Multivariate logistic regression models were used to estimate odds ratios and 95% confidence intervals. RESULTS: Workers 41 years and older were more likely to have experienced severe shoulder sprain/strain injuries [Age 41-50: OR = 3.62, 95% CI: 1.71-7.65; age 51 and older: OR = 4.49, 95% CI: 1.89-10.67] and severe back sprain/strain injuries [Age 41-50: OR = 1.70, 95% CI: 1.06-2.33; age 51 and older: OR = 1.5, 95% CI: 0.90-2.52]. Line workers and maintenance workers had an increased risk of serious sprain/strain injuries. Gender and day of week were not significantly associated with sprain/strain injuries. DISCUSSION: Though this study is limited by available data, future studies may benefit from this preliminary examination of occupational and demographic characteristics associated with serious sprain/strain injuries among electric utility workers.

Thermal burn and electrical injuries among electric utility workers, 1995-2004.

This study describes the occurrence of work-related injuries from thermal-, electrical- and chemical-burns among electric utility workers. We describe injury trends by occupation, body part injured, age, sex, and circumstances surrounding the injury. This analysis includes all thermal, electric, and chemical injuries included in the Electric Power Research Institute (EPRI) Occupational Health and Safety Database (OHSD). There were a total of 872 thermal burn and electric shock injuries representing 3.7% of all injuries, but accounting for nearly 13% of all medical claim costs, second only to the medical costs associated with sprain- and strain-related injuries (38% of all injuries). The majority of burns involved less than 1 day off of work. The head, hands, and other upper extremities were the body parts most frequently injured by burns or electric shocks. For this industry, electric-related burns accounted for the largest percentage of burn injuries, 399 injuries (45.8%), followed by thermal/heat burns, 345 injuries (39.6%), and chemical burns, 51 injuries (5.8%). These injuries also represented a disproportionate number of fatalities; of the 24 deaths recorded in the database, contact with electric current or with temperature extremes was the source of seven of the fatalities. High-risk occupations included welders, line workers, electricians, meter readers, mechanics, maintenance workers, and plant and equipment operators.

Occupational injury surveillance among electric utility employees.

Currently, there are only limited injury surveillance data for the electric utility workforce. To address this gap, an Occupational Health Surveillance Database for electric power utilities was established for epidemiologic monitoring and intervention program evaluation. Injury rates varied across utility occupations, such as, managers, line workers, and meter readers, ranging from 0.18 to 9.63 per 100 employee-years based on more than 500,000 employee-years of observation. Compared with male workers, the risk of injury among female workers was lower overall, although their risk was higher in nonoffice occupations than their male counterparts. Across the period 2000 to 2002, three of four companies that experienced decreases in workforce size also experienced noticeable increases in injury rates. Our results suggest that benchmarking and prevention efforts should be directed at specific occupational groups and specific injury types.

Fungal types and concentrations from settled dust in normal residences.

Analysis of settled dust collected from carpeting and furnishings is occasionally used by investigators to determine whether an environment contains unusual fungi. Little information is available concerning the types and concentrations of culturable fungi present on textile surfaces in normal residential settings not affected by unusual mold reservoirs, such as from fungal growth sites within the built environment. This study presents the results of the collection and analysis of surface dust from 26 residential environments that were prescreened by interview, physical inspection, and air sampling to limit the surface dust collection to structures in which there was no history of water intrusion, flooding, plumbing leaks, signs of mold growth, or evidence of unusual airborne fungal spore types or concentrations. In those structures found to have no history or indications of water events or unusual fungi, surface dust was vacuumed from prescribed horizontal areas on carpet and textile-covered furnishings. These samples were then subjected to fungal culture, from which viable colonies were enumerated and identified. Based on the study results, it does not appear reasonable that the frequently quoted total fungi concentration exceeding 10(5) CFU/g is definitive evidence that a residential surface is contaminated with unusual amounts of culturable fungi. Collocated samples collected from eight side-by-side carpets sections revealed poor reproducibility. While settled dust sampling may be appropriate for determining the fungal status of a localized area, or as a gross screening tool, using settled dust results alone to establish the presence of unusual fungal types or concentrations within a structure appears to be inappropriate, and using settled dust results with other investigative methods, such as visual observations and air sampling, requires cautious interpretation.

Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a "state-of-the-art" review.

Throughout the history of automobile development, chrysotile asbestos has been an essential component of vehicle brake linings and pads. Acceptable alternatives were not fully developed until the 1980s, and these were installed in vehicles produced over the past decade. This article presents a "state-of-the-art" analysis of what was known over time about the potential environmental and occupational health hazards associated with the presence of chrysotile asbestos in brake linings and pads. As part of this analysis, the evolution of automobile brakes and brake friction materials, beginning with the early 1900s, is described. Initial concerns regarding exposures to asbestos among workers involved in the manufacture of friction products were raised as early as 1930. Between 1930 and 1959, eight studies were conducted for which friction product manufacturing workers were part of the population assessed. These studies provided evidence of asbestosis among highly exposed workers, but provided little information on the magnitude of exposure. The U.S. Public Health Service proposed the first occupational guideline for asbestos exposure in 1938. The causal relationship between asbestos exposure and lung cancer was confirmed in 1955 in asbestos textile workers in the United Kingdom, and later, in 1960, in South Africa, mesothelioma was attributed to asbestos exposure to even relatively low airborne concentrations of crocidolite. Between 1960 and 1974, five epidemiology studies of friction product manufacturing workers were conducted. During this same time period, the initial studies of brake lining wear (dust or debris) emissions were conducted showing that automobile braking was not a substantial contributor of asbestos fibers greater than 5 microm in length to ambient air. The first exposure surveys, as well as preliminary health effects studies, for brake mechanics were also conducted during this period. In 1971, the Occupational Safety and Health Administration promulgated the first national standards for workplace exposure to asbestos. During the post-1974 time period, most of the information on exposure of brake mechanics to airborne asbestos during brake repair was gathered, primarily from a series of sampling surveys conducted by the National Institute of Occupational Safety and Health in the United States. These surveys indicated that the time-weighted average asbestos