Drugs derived from phage display: From candidate identification to clinical practice

Phage display, one of today’s fundamental drug discovery technologies, allows identification of a broad range of biological drugs, including peptides, antibodies and other proteins, with the ability to tailor critical characteristics such as potency, specificity and cross-species binding. Further, unlike in vivo technologies, generating phage display-derived antibodies is not restricted by immunological tolerance. Although more than 20 phage display-derived antibody and peptides are currently in late-stage clinical trials or approved, there is little literature addressing the specific challenges and successes in the clinical development of phage-derived drugs. This review uses case studies, from candidate identification through clinical development, to illustrate the utility of phage display as a drug discovery tool, and offers a perspective for future developments of phage display technology.     

Targeting mesenchymal stem cell therapy for severe pneumonia patients

Pneumonia is the inflammation of the lungs and it is the world’s leading cause of death for children under 5 years of age.The latest coronavirus disease 2019(COVID-19)virus is a prominent culprit to severe pneumonia.With the pandemic running rampant for the past year,more than 1590000 deaths has occurred worldwide up to December 2020 and are substantially attributable to severe pneumonia and induced cytokine storm.Effective therapeutic approaches in addition to the vaccines and drugs under development are hence greatly sought after.Therapies harnessing stem cells and their derivatives have been established by basic research for their versatile capacity to specifically inhibit inflammation due to pneumonia and prevent alveolar/pulmonary fibrosis while enhancing antibacterial/antiviral immunity,thus significantly alleviating the severe clinical conditions of pneumonia.In recent clinical trials,mesenchymal stem cells have shown effectiveness in reducing COVID-19-associated pneumonia morbidity and mortality;positioning these cells as worthy candidates for combating one of the greatest challenges of our time and shedding light on their prospects as a nextgeneration therapy to counter future challenges.     

Dogs Detect Larger Wind Energy Effects on Bats and Birds

As wind turbine-caused mortality of birds and bats increases with increasing wind energy capacity, accurate fatality estimates are needed to assess effects, identify collision factors, and formulate mitigation. Finding a larger proportion of collision victims reduces the magnitude of adjustment for the proportion not found, thus reducing opportunities for bias. We tested detection dogs in trials of bat and small-bird carcasses placed randomly in routine fatality monitoring at the Buena Vista and Golden Hills Wind Energy projects, California, USA, 2017. Of trial carcasses placed and confirmed available before next-day fatality searches, dogs detected 96% of bats and 90% of small birds, whereas humans at a neighboring wind project detected 6% of bats and 30% of small birds. At Golden Hills dogs found 71 bat fatalities in 55 searches compared to 1 bat found by humans in 69 searches within the same search plots over the same season. Dog detection rates of trial carcasses remained unchanged with distance from turbine, and dogs found more fatalities than did humans at greater distances from turbines. Patterns of fatalities found by dogs within search plots indicated 20% of birds and 4–14% of bats remained undetected outside search plots at Buena Vista and Golden Hills. Dogs also increased estimates of carcass persistence by finding detection trial carcasses that the trial administrator had erroneously concluded were removed. Compared to human searches, dog searches resulted in fatality estimates up to 6.4 and 2.7 times higher for bats and small birds, respectively, along with higher relative precision and >90% lower cost per fatality detection. © 2020 The Authors. The Journal of Wildlife Management published by Wiley Periodicals, Inc. on behalf of The Wildlife Society.     

Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection: Methods,simulation model and their implementation in R

Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd , previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so-called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked-up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies.     

PA-CRM: A continuous reassessment method for pediatric phase I oncology trials with concurrent adult trials

Pediatric phase I trials are usually carried out after the adult trial testing the same agent has started, but not completed yet. As the pediatric trial progresses, in light of the accrued interim data from the concurrent adult trial, the pediatric protocol often is amended to modify the original pediatric dose escalation design. In practice, this is done frequently in an ad hoc way, interrupting patient accrual and slowing down the trial. We developed a pediatric-continuous reassessment method (PA-CRM) to streamline this process, providing a more efficient and rigorous method to find the maximum tolerated dose for pediatric phase I oncology trials. We use a discounted joint likelihood of the adult and pediatric data, with a discount parameter controlling information borrowing between pediatric and adult trials. According to the interim adult and pediatric data, the discount parameter is adaptively updated using the Bayesian model averaging method. Numerical study shows that the PA-CRM improves the efficiency and accuracy of the pediatric trial and is robust to various model assumptions.     

Hsp90: Still a viable target in prostate cancer

Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer, including the androgen receptor. Despite robust preclinical data demonstrating anti-tumor activity of first-generation Hsp90 inhibitors in prostate cancer, poor clinical responses initially cast doubt over the clinical utility of this class of agent. Recent advances in compound design and development, use of novel preclinical models and further biological insights into Hsp90 structure and function have now stimulated a resurgence in enthusiasm for these drugs as a therapeutic option. This review highlights how the development of new-generation Hsp90 inhibitors with improved physical and pharmacological properties is unfolding, and discusses the potential contexts for their use either as single agents or in combination, for men with metastatic prostate cancer.     

Microbially enhanced oil recovery from carbonate reservoirs

About half of the world's oil production is from carbonate formations. However, most of the research in microbially enhanced oil recovery (MEOR), a potentially important tertiary recovery technology, has focused on sandstone reservoirs because, in general, they are geologically simpler than carbonate reservoirs and easier to model in the laboratory. Carbonate formations have a wide range of pore geometries and distributions, resulting in complex flow dynamics. The low matrix permeabilities and the dual porosity characteristics of most carbonate formations, coupled with the chemistry of carbonates, have slowed implementation of enhanced oil recovery methods. A review of the data on carbonate reservoirs in Dwight's Energydata TOTL System indicated that 40% of the oil‐producing carbonate reservoirs surveyed in the United States have environmental, geological, and petrophysical conditions that would make them candidates for MEOR. A review of a number of MEOR field trials showed that rates of oil production could be increased by as much as 200%. Microbial activity in these trials was probably due to that of indigenous populations rather than the microorganisms injected for the trials. Detrimental effects such as loss of injectivity and increased souring were not reported. Based on analysis of the geology and petrophysical characteristics of carbonates, two common mechanisms of MEOR, microbial acid production and microbial gas production, are especially suited for application in carbonate reservoirs.     

Factors affecting incidence and severity of leaf spot disease on lettuce caused by Septoria birgitae

In the 1990s during wet seasons a new disease causing brown leaf spots on lettuce (Lactuca sativa) was found for the first time in many lettuce‐growing areas of Austria and Germany. The causal agent, a new pathogenic species called Septoria birgitae, may be responsible for total crop loss. To study how temperature, inoculum density and leaf wetness period influence disease incidence and severity of leaf spot on lettuce caused by S. birgitae, we carried out in vivo experiments in growth chambers and in the field. Additionally, we evaluated the relevance of infected plant debris acting as a primary inoculum source in soil for subsequent crops. S. birgitae produces spores over a wide temperature range between 5°C and 30°C, and can infect plants at temperatures between 10°C and 30°C, with an optimum between 20°C and 30°C. Spores of S. birgitae at a density of at least 10³ conidia mL^–1 are essential for disease outbreak on lettuce. Because leaf wetness is crucial for releasing conidia from pycnidia, we studied the impact of leaf wetness duration on disease development under various temperature conditions. For relevant leaf spot disease development on lettuce in vivo, a leaf wetness duration of at least 24 h and temperatures higher than 10°C were necessary. Leaf spot disease development in the field required several leaf wetness periods longer than 20 h at approximately 15°C at the beginning of crop cultivation. Incorporating S. birgitae infected plant debris in soil as a primary inoculum was not relevant for leaf spot disease outbreak in the next year. However, in cases of continuous cropping of lettuce on the same field and in the same season, Septoria‐infected lettuce debris may become more relevant.