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Key Points Immunomodulatory biologics are a class of biotechnology-derived therapeutic products that are designed to engage immune-relevant targets and are indicated in the treatment and management of a range of diseases, including immune-mediated inflammatory diseases and malignancies. Despite their high specificity and therapeutic advantages, immmunomodulatory biologics have been associated with adverse reactions such as serious infections, malignancies and cytokine release syndrome, which arise owing to the on-target or exaggerated pharmacological effects of these drugs. Immunogenicity resulting in the generation of antidrug antibodies is another unwanted effect that leads to loss of efficacy and — rarely — hypersensitivity reactions. For some adverse reactions, mitigating and preventive strategies are in place, such as stratifying patients on the basis of responsiveness to therapy and the risk of developing adverse reactions. These strategies depend on the availability of robust biomarkers for therapeutic efficacy and the risk of adverse reactions: for example, seropositivity for John Cunningham virus is a risk factor for progressive multifocal leukoencephalopathy. The development of effective biomarkers will greatly aid these strategies. The development and design of safer immunomodulatory biologics is reliant on a detailed understanding of the nature of the disease, target biology, the interaction of the target with the immunomodulatory biologic and the inherent properties of the biologic that elicit unwanted effects. The availability of in vitro and in vivo models that can be used to predict adverse reactions associated with immunomodulatory biologics is central to the development of safer immunomodulatory biologics. Some progress has been made in developing in vitro and in silico tests for predicting cytokine release syndrome and immunogenicity, but there is still a lack of models for effectively predicting infections and malignancies. Two pathways can be followed in designing and developing safer immunomodulatory biologics. The first pathway involves generating a biologic that engages an alternative target or mechanism to produce the desired pharmacodynamic effect without the associated adverse reaction, and is followed when the adverse reaction cannot be dissociated from the target biology. The second pathway involves redesigning the biologic to 'engineer out' components within the biologic structure that trigger adverse effects or to alter the nature of the target–biologic interactions. Owing to their specificity, immunomodulatory biologics generally have better safety profiles than small-molecule drugs. However, adverse effects such as an increased risk of infections or cytokine release syndrome are of concern. Here, Park and colleagues discuss the current strategies used to predict and mitigate these adverse effects and consider how they can be used to inform the development of safer immunomodulatory biologics. Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions — including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity — pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.

Abstract Background An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814—the prodrug (lufotrelvir) and its active moiety (PF-00835231)—is a potent inhibitor of the SARS-CoV-2 3CL protease. Method Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167. Single and multiple ascending PF-07304814 (lufotrelvir) infusions were generally safe and well tolerated in participants hospitalized with COVID-19. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250 and 500 mg/d, respectively.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment. The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Immunomodulatory biologies, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions --including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity--pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.

The EMBO conference/FEBS advanced course, Europhosphatases Conference 2005, on The Biology of Phosphatases, was held in Churchill College, Cambridge University, UK, July 10-14 2005. Although the identity of each of the protein phosphatase genes in the human genome is now known, the challenges of determining the enzymes interacting partners, mechanisms of regulation, physiological substrates, biological roles and their links to disease remain substantial.

Abstract COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment. Competing Interest Statement A.D.M has a sponsored program contract with Pfizer to test compounds for inhibition of coronavirus proteases. JW has a sponsored research agreement with Pfizer to test compounds for inhibition of coronavirus proteases. The Frieman Laboratory was funded by Pfizer for the work in this manuscript. Footnotes * One Sentence Summary: PF-07304814, a novel phosphate prodrug is disclosed as an investigational novel intravenous small molecule 3CL protease inhibitor for the potential treatment of COVID-19 and other coronavirus infections. * One small typo in the abstract. The compound ID number should be PF-00835231 and in the abstract the number is PF-00835321 in one place. This has been corrected in the abstract and in the manuscript. Version 3: Added in vivo efficacy data, section Activity of PF-00835231 in a mouse model of SARS-CoV-1 infection and Figure 4.

SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation. The COVID Human Genetic Effort examines the molecular, cellular and immunological determinants of the various SARS-CoV-2-related disease manifestations by searching for causal errors of immunity.

Background The imperative to improve global health has prompted transnational research partnerships to investigate common health issues on a larger scale. The Global Alliance for Chronic Diseases (GACD) is an alliance of national research funding agencies. To enhance research funded by GACD members, this study aimed to standardise data collection methods across the 15 GACD hypertension research teams and evaluate the uptake of these standardised measurements. Furthermore we describe concerns and difficulties associated with the data harmonisation process highlighted and debated during annual meetings of the GACD funded investigators. With these concerns and issues in mind, a working group comprising representatives from the 15 studies iteratively identified and proposed a set of common measures for inclusion in each of the teams’ data collection plans. One year later all teams were asked which consensus measures had been implemented. Results Important issues were identified during the data harmonisation process relating to data ownership, sharing methodologies and ethical concerns. Measures were assessed across eight domains; demographic; dietary; clinical and anthropometric; medical history; hypertension knowledge; physical activity; behavioural (smoking and alcohol); and biochemical domains. Identifying validated measures relevant across a variety of settings presented some difficulties. The resulting GACD hypertension data dictionary comprises 67 consensus measures. Of the 14 responding teams, only two teams were including more than 50 consensus variables, five teams were including between 25 and 50 consensus variables and four teams were including between 6 and 24 consensus variables, one team did not provide details of the variables collected and two teams did not include any of the consensus variables as the project had already commenced or the measures were not relevant to their study. Conclusions Deriving consensus measures across diverse research projects and contexts was challenging. The major barrier to their implementation was related to the time taken to develop and present these measures. Inclusion of consensus measures into future funding announcements would facilitate researchers integrating these measures within application protocols. We suggest that adoption of consensus measures developed here, across the field of hypertension, would help advance the science in this area, allowing for more comparable data sets and generalizable inferences.