Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotypematched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.monoclonal antibody | developability | biophysical properties | manufacturability | nonspecificity T arget binding is the predominant first concern in development of any drug. However, once a lead molecule attains the desired potency of biological modification, a suite of characteristics termed "developability" assumes critical importance. For monoclonal antibodies, these properties include high-level expression, high solubility, covalent integrity, conformational and colloidal stability, low polyspecificity, and low immunogenicity. The high cost of failing any of these criteria at a late stage in drug development has led to considerable efforts at predicting developability on the basis of sequence motifs and experimentally determined biophysical properties (1-15).In a landmark study of small-molecule drugs over 2,000 molecules with United States Adopted Names (USAN) designations and known to have oral availability were collected and computationally analyzed (16). A simple set of thresholds, encapsulated as the "Lipinski rule of fives," was formulated and has been used by many to prioritize small molecules for entry into clinical development. To date, analogous guiding principles for antibody drugs have not emerged-we therefore endeavor here to do so. By analogy to the Lipinski effort, we first collected the sequences of antibodies that had reached at least phase-2 trials and had USAN or WHO International Nonproprietary Names (INN) designations (137 in total as of the start of this project). As a common basis for comparison of intrinsic variable domain phenotypes we expressed each antibody as the human IgG1 isotype and formulated them in simple Hepes-buffered saline. Each antibody was then subjected to a battery of 12 different biophysical assays in common use for developability assessment.Unexpectedly, for many of the measures the distribution of values was not symmetrically Gaussian, but instead was lon...

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The recognition of occupational carcinogens is important for primary prevention, compensation and surveillance of exposed workers, as well as identifying causes of cancer in the general population. This study updates previously published lists of known occupational carcinogens while providing additional information on cancer type, exposure scenarios and routes, and discussing trends in the identification of carcinogens over time. Data were extracted from International Agency for Research on Cancer (IARC) Monographs covering the years 1971–2017, using specific criteria to ensure occupational relevance and provide high confidence in the causality of observed exposure-disease associations. Selected agents were substances, mixtures or types of radiation classified in IARC Group 1 with ‘sufficient evidence of carcinogenicity’ in humans from studies of exposed workers and evidence of occupational exposure documented in the pertinent monograph. The number of known occupational carcinogens has increased over time: 47 agents were identified as known occupational carcinogens in 2017 compared with 28 in 2004. These estimates are conservative and likely underestimate the number of carcinogenic agents present in workplaces. Exposure to these agents causes a wide range of cancers; cancers of the lung and other respiratory sites, followed by skin, account for the largest proportion. The dominant routes of exposure are inhalation and dermal contact. Important progress has been made in identifying occupational carcinogens; nevertheless, there is an ongoing need for research on the causes of work-related cancer. Most workplace exposures have not been evaluated for their carcinogenic potential due to inadequate epidemiologic evidence and a paucity of quantitative exposure data.

ObjectivesTo estimate the numbers of workers exposed to known and suspected occupational carcinogens in Canada, building on the methods of CARcinogen EXposure (CAREX) projects in the European Union (EU).MethodsCAREX Canada consists of estimates of the prevalence and level of exposure to occupational carcinogens. CAREX Canada includes occupational agents evaluated by the International Agency for Research on Cancer as known, probable or possible human carcinogens that were present and feasible to assess in Canadian workplaces. A Canadian Workplace Exposure Database was established to identify the potential for exposure in particular industries and occupations, and to create exposure level estimates among priority agents, where possible. CAREX EU data were reviewed for relevance to the Canadian context and the proportion of workers likely to be exposed by industry and occupation in Canada was assigned using expert assessment and agreement by a minimum of two occupational hygienists. These proportions were used to generate prevalence estimates by linkage with the Census of Population for 2006, and these estimates are available by industry, occupation, sex and province.ResultsCAREX Canada estimated the number of workers exposed to 44 known, probable and suspected carcinogens. Estimates of levels of exposure were further developed for 18 priority agents. Common exposures included night shift work (1.9 million exposed), solar ultraviolet radiation exposure (1.5 million exposed) and diesel engine exhaust (781 000 exposed).ConclusionsA substantial proportion of Canadian workers are exposed to known and suspected carcinogens at work.

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

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We used data on number of carcasses of wildlife species sold in 79 bushmeat markets in a region of Nigeria and Cameroon to assess whether species composition of a market could be explained by anthropogenic pressures and environmental variables around each market. More than 45 mammal species from 9 orders were traded across all markets; mostly ungulates and rodents. For each market, we determined median body mass, species diversity (game diversity), and taxa that were principal contributors to the total number of carcasses for sale (game dominance). Human population density in surrounding areas was significantly and negatively related to the percentage ungulates and primates sold in markets and significantly and positively related to the proportion of rodents. The proportion of carnivores sold was higher in markets with high human population densities. Proportion of small-bodied mammals (<1 kg) sold in markets increased as human population density increased, but proportion of large-bodied mammals (>10 kg) decreased as human population density increased. We calculated an index of game depletion (GDI) for each market from the sum of the total number of carcasses traded per annum and species, weighted by the intrinsic rate of natural increase (rmax ) of each species, divided by individuals traded in a market. The GDI of a market increased as the proportion of fast-reproducing species (highest rmax ) increased and as the representation of species with lowest rmax (slow-reproducing) decreased. The best explanatory factor for a market's GDI was anthropogenic pressure-road density, human settlements with >3000 inhabitants, and nonforest vegetation. High and low GDI were significantly differentiated by human density and human settlements with >3000 inhabitants. Our results provided empirical evidence that human activity is correlated with more depleted bushmeat faunas and can be used as a proxy to determine areas in need of conservation action.

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