Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors.

PURPOSE: Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers. EXPERIMENTAL DESIGN: We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP). RESULTS: HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans. CONCLUSIONS: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

Living with plague: Lessons from the Soviet Union's antiplague system.

Zoonoses, such as plague, are primarily animal diseases that spill over into human populations. While the goal of eradicating such diseases is enticing, historical experience validates abandoning eradication in favor of ecologically based control strategies (which reduce morbidity and mortality to a locally accepted risk level). During the 20th century, one of the most extensive plague-eradication efforts in recorded history was undertaken to enable large-scale changes in land use in the former Soviet Union (including vast areas of central Asia). Despite expending tremendous resources in its attempt to eradicate plague, the Soviet antiplague response gradually abandoned the goal of eradication in favor of plague control linked with developing basic knowledge of plague ecology. Drawing from this experience, we combine new gray-literature sources, historical and recent research, and fieldwork to outline best practices for the control of spillover from zoonoses while minimally disrupting wildlife ecosystems, and we briefly compare the Soviet case with that of endemic plague in the western United States. We argue for the allocation of sufficient resources to maintain ongoing local surveillance, education, and targeted control measures; to incorporate novel technologies selectively; and to use ecological research to inform developing landscape-based models for transmission interruption. We conclude that living with emergent and reemergent zoonotic diseases-switching to control-opens wider possibilities for interrupting spillover while preserving natural ecosystems, encouraging adaptation to local conditions, and using technological tools judiciously and in a cost-effective way.

Entangled histories of plague ecology in Russia and the USSR.

During the mid-twentieth century, Soviet scientists developed the "natural focus" theory-practice framework to explain outbreaks of diseases (such as bubonic plague) endemic to wild animals and transmitted to humans. Focusing on parasitologist-physician Evgeny N. Pavlovsky and other field scientists' work in the Soviet borderlands, this article explores how the natural focus framework's concepts and practices were entangled in political as well as material ecologies of knowledge and practice. We argue that the very definition of endemic plague incorporated both hands-on materialist experience (including the identification of microbes/pathogens, insects/vectors, and mammals/reservoirs) and ideological concepts that supported Soviet colonization ("improving" hinterlands, "controlling natural focuses of disease," and "sanitizing" landscapes). Theorizing and fighting plague assisted with the goals of controlling and improving landscapes and peoples in southern Russia and Central Asia. The history of the natural focus framework illustrates how Soviet disease ecology co-developed with the needs of local and central political powers in the Soviet borderlands.

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.

Population Cycles, Disease, and Networks of Ecological Knowledge.

Wildlife populations in the northern reaches of the globe have long been observed to fluctuate or cycle periodically, with dramatic increases followed by catastrophic crashes. Focusing on the early work of Charles S. Elton, this article analyzes how investigations into population cycles shaped the development of Anglo-American animal ecology during the 1920s-1930s. Population cycling revealed patterns that challenged ideas about the "balance" of nature; stimulated efforts to quantify population data; and brought animal ecology into conversation with intellectual debates about natural selection. Elton used the problem of understanding wildlife population cycles to explore a central tension in ecological thought: the relative influences of local conditions (food supply, predation) and universal forces (such as climate change and natural selection) in regulating wild animal populations. He also sought patronage and built research practices and the influential Bureau of Animal Population around questions of population regulation during the 1930s. Focusing on disease as a local population regulator that could interact with global climatic influences, Elton facilitated an interdisciplinary and population-based approach in early animal ecology. Elton created a network of epidemiologists, conservationists, pathologists and mathematicians, who contributed to population cycle research. I argue that, although these people often remained peripheral to ecology, their ideas shaped the young discipline. Particularly important were the concepts of abundance, density, and disease; and the interactions between these factors and natural selection. However, Elton's reliance on density dependence unwittingly helped set up conditions conducive to the development of controversies in animal ecology in later years. While ecologists did not come to consensus on the ultimate causes of population cycles, this phenomenon was an important early catalyst for the development of theory and practice in animal ecology.

The Immunotherapeutics and Vaccine Summit - CHI's fifth annual meeting - novel vaccines: adjuvants and delivery systems: part 2.

The Fifth Annual Immunotherapeutics and Vaccine Summit (ImVacS), held in Boston, included topics covering new developments in the field of adjuvants and delivery systems for vaccines. This conference report highlights selected presentations on vaccines for infectious diseases, the use of adenovirus 5 (Ad5) for oral vaccination, modes of delivery for vaccines, and the strategy of DNA vaccination.

Anthrax in transit; practical experience and intellectual exchange.

Focusing on three Anglo-American outbreaks of industrial anthrax, this essay engages the question of how local circumstances influenced the transmission of scientific knowledge in the late nineteenth century. Walpole (Massachusetts), Glasgow, and Bradford (Yorkshire) served as important nodes of transnational investigation into anthrax. Knowledge about the morphology and behavior of Bacillus anthracis changed little while in transit between these nodes, even during complex debates about the nature of bacterial morphology, disease causation, and spontaneous generation. Working independently of their more famous counterparts (Robert Koch and Louis Pasteur), Anglo-American anthrax investigators used visual representations of anthrax bacilli to persuade their peers that a specific, identifiable cause produced all forms of anthrax-malignant pustule (cutaneous anthrax), intestinal anthrax, and woolsorter's disease (pneumonic anthrax). By the late 1870s, this point of view also supported what we would today call an ecological notion of the disease's origins in the interactions of people, animals, and microorganisms in the context of global commerce.

Mapping a zoonotic disease: Anglo-American efforts to control bovine tuberculosis before World War I.

Before World War I, British and American public health officials correlated tuberculosis in dairy cattle with severe infections in milk-drinking children. They traced bacteria in municipal milk supplies, mapped the locations of infected animals, and sought regulatory power to destroy them. Consumers, milk producers, municipal officials, veterinarians, and physicians all influenced the shape of antituberculosis regulations. Many condemned pasteurization as too costly and as masking tubercular contamination and poor sanitation. They saw milk-borne tuberculosis as an environmental as well as a bacteriological problem. Similar to other zoonotic diseases such as BSE, bovine tuberculosis blurred the boundaries between urban and rural, production and consumption, and human and animal bodies.

Female genital mutilation in developing countries: an agenda for public health response.

There is uncertainty regarding reasons for persistence of the practice of female genital mutilation (FGM) and the best strategies for intervening effectively. In spite of strong international condemnation, the persistence of FGM in many countries suggests that it can only be effectively eliminated when its practitioners are presented with a safe alternative that preserves their culture and, at the same time, protects the health and well being of women. Recognizing that there is no simple solution to the problem, this paper argues that interventions for preventing FGM should be non-directive, culture-specific and multi-faceted to be of practical relevance. Such interventions should not only motivate change, but should also help communities to establish practical means by which that change can occur. Potentially effective prevention interventions targeted at local practitioners of FGM, parents, at-risk adolescents, health and social workers, governments, religious authorities, the civil society, and communities are presented.