A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule.

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule's mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT3L-Fc. In addition to the preclinical PK data of FLT3L-Fc in cynomolgus monkeys, clinical PK and PD data from other FLT3-agonist molecules (GS-3583 and CDX-301) were used to inform the model and project the expansion profiles of conventional DC1s (cDC1s) and total DCs in peripheral blood. This work constitutes an essential part of our model-informed drug development (MIDD) strategy for clinical development of FLT3L-Fc by projecting PK/PD in healthy volunteers, determining the first-in-human (FIH) dose, and informing the efficacious dose in clinical settings. Model-generated results were incorporated in regulatory filings to support the rationale for the FIH dose selection.

Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey.

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science.

Nonclinical pharmacokinetics, pharmacodynamics and safety assessment of a FLT3L-Fc molecule for cancer immunotherapy.

FLT3L-Fc is a cytokine-Fc fusion agonizing receptor-type tyrosine-protein kinase FLT3 (fms-related tyrosine kinase 3; CD135). FLT3 is expressed on dendritic cells (DCs) as well as myeloid and lymphoid progenitors. Nonclinical pharmacokinetics, pharmacodynamics and safety of FLT3L-Fc were investigated in rats and cynomolgus monkeys. FLT3L-Fc induced robust pharmacodynamic responses, evidenced by marked expansion of peripheral blood cDC1s, cDC2s, and pDCs (up to 301-fold in rats and 378-fold in monkeys), peaking at 8-10 days after the first dose. FLT3L-Fc was well tolerated with no adverse findings at doses up to 10 mg/kg administered intravenously twice three weeks apart. In both species, major clinical pathology findings consisted of expansion of white blood cell (WBC) populations including lymphocytes, monocytes, neutrophils, basophils, and large unstained cells, which were pronounced after the first dose. The WBC findings were associated microscopically with histiocytic and mononuclear cell infiltrates in multiple organs. Tissue immunohistochemistry in monkeys showed that the leukocyte infiltrates consisted of hematopoietic progenitor cells and histiocytes with a reactive morphology and were associated with a slight stimulation of regional T and B cell populations. Additional FLT3L-Fc-associated changes included decreases in red blood cell (RBC) mass, increases in RBC distribution width, variable changes in reticulocytes, and transient alterations in platelet counts (rats only). The RBC and WBC findings were associated microscopically with increased hematopoietic cellularity of the bone marrow in both species and increased splenic megakaryocytic extramedullary hematopoiesis in rats. The totality of nonclinical safety data support the clinical development of FLT3L-Fc.

Successful Development of Nonclinical Anti-Drug Antibody Assays to Support Zinpentraxin Alfa Reproductive Toxicology Studies.

Immunogenicity assessment is an essential part of biotherapeutic drug development. While the immune response in animals is not always representative of the human immune response, immunogenicity data obtained in animal models is still informative for the evaluation of drug exposure and safety. The most common assay format used for the detection of anti-drug antibodies (ADAs) in preclinical and clinical studies is the bridging format. The advantage of this method is that it can detect all antibody isotypes generated against the therapeutic. However, the method development can be time-consuming and labor-intensive, due to the need for labeling of the drug which is used both as capture and detection. Various generic ADA assays have been successfully implemented to overcome these disadvantages and to enable faster assay development timelines to support nonclinical toxicology studies. Here, we describe the challenges in the development of an assay to detect antibodies to zinpentraxin alfa, a recombinant human pentraxin-2, in rabbit and rat toxicology studies. Our initial efforts to develop a bridging assay failed, prompting us to develop a method adapted from generic assay formats to detect anti-zinpentraxin alfa antibodies in the serum of different species with minimal optimization. However, while the general assay format remained similar, assay reagents were adapted between the different species, resulting in the development of two distinct assays for the detection of ADAs in rat and rabbit. Here, we share the final development/validation data and the immunogenicity study results. Our work highlights the need for the evaluation of alternate assay formats when evaluating novel drug modalities.

Repeat-dose and embryo-fetal developmental toxicity of zinpentraxin alfa.

Zinpentraxin alfa is a recombinant human pentraxin-2 (PTX-2) developed for the treatment of various fibrotic diseases with the hypothesis that supplementing endogenous PTX-2 levels through intravenous administration should increase its regulatory capacity in circulation and at the site of disease, thereby promoting healing and reducing fibrosis. Zinpentraxin alfa has been studied in various clinical trials, particularly in patients with idiopathic pulmonary fibrosis, where it has demonstrated efficacy in slowing decline in lung function in a phase 2 study. In the present investigation, we summarize findings from 14-day repeat-dose toxicity studies in rats and cynomolgus monkeys supporting early clinical development of zinpentraxin alfa. In addition, we also describe the findings from the embryo-fetal developmental (EFD) studies conducted in rats and rabbits, since the intended fibrosis patient population may include patients of childbearing potential. Zinpentraxin alfa was well tolerated by rats and monkeys in general toxicity studies with no treatment-related adverse effects, as well as by pregnant rats over the same dose range in a definitive EFD study. In contrast, substantial toxicity was observed in a rabbit dose-range-finder EFD study. Zinpentraxin alfa was poorly tolerated by pregnant rabbits and effects on the dams correlated with post-implantation fetal losses. The disparate effects of zinpentraxin alfa on embryo-fetal development between the two species suggests a potential unknown biological function of PTX-2 in pregnancy in the rabbit, which may be relevant to humans. Our findings warrant the consideration for highly effective contraceptive measures to avoid pregnancy in patients enrolled in clinical studies with zinpentraxin alfa.

Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease.

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

Mortality and morbidity in outborn extremely low birth weight neonates: a retrospective analysis.

OBJECTIVE: We aimed to identify differences in morbidity and mortality between inborn versus outborn extremely low birth weight (ELBW) infants admitted to the Texas Children's Hospital neonatal intensive care unit (NICU). STUDY DESIGN: Vermont Oxford Network data were analyzed between January 2014 and December 2017. Inborn versus outborn outcomes were compared. RESULT: Of 533 ELBW infants, 402 were inborn, and 131 were outborn. Gestational age and birth weight (BW) were similar. After adjusting outcomes to control for maternal steroids, maternal hypertension, maternal prenatal care, and temperature below 36 °C at admission, no outcomes were significantly different except inborn patients had decreased odds of late onset sepsis (adjusted odds ratio = 0.606, 95% confidence interval: 0.377-0.973, p = 0.038). CONCLUSION: In this study, outborn ELBW patients had increased odds of late onset sepsis compared with inborn ELBW patients after controlling for covariates that differed significantly between these two cohorts.

In Vivo Assessment of Antibody-Dependent Enhancement of Influenza B Infection.

A theoretical safety concern proposed in the influenza literature is that therapeutic antiviral antibodies could have the potential for antibody-dependent enhancement (ADE) of infection and disease. ADE may occur when virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake and, in some cases, enhance replication, which can lead to an exacerbation of virus-mediated disease. Alternatively, ADE may occur due to antibody-dependent complement activation exacerbating virus-mediated disease in the absence of increased replication. As a result of this theoretical safety concern, safety assessment of anti-influenza antibodies may include an in vivo evaluation of ADE of infection and/or disease. These studies were conducted to investigate the potential of MHAB5553A, a broadly specific, neutralizing therapeutic anti-influenza B antibody, to elicit ADE of infection and disease in mouse models of influenza B infection. In parallel studies, female DBA/2J mice were infected with either influenza B/Victoria/504/2000 or influenza B/Brisbane/60/2008 representing distinct lineages. Assessment of ADE was based on an integration of results from multiple endpoints, including infectious lung viral titers and genomes, body weight, mortality, lung weight, and histopathology. In these studies, the high dose of 15 mg/kg MHAB5553A resulted in substantial attenuation of influenza pneumonia, with more modest effects at 1.5 mg/kg; whereas MHAB5553A treatment at 0.15 or 0.015 mg/kg was generally comparable to vehicle-treated controls. Our results demonstrate that MHAB5553A across a broad range of doses did not enhance primary influenza B infection or disease in this model, and represent a nonclinical de-risking of the ADE potential with this antibody.

T cell LFA-1-induced proinflammatory mRNA stabilization is mediated by the p38 pathway kinase MK2 in a process regulated by hnRNPs C, H1 and K.

Activation of the ß2 integrin lymphocyte function-associated antigen-1 (LFA-1) in T cells induces stabilization of proinflammatory AU-rich element (ARE)-bearing mRNAs, by triggering the nuclear-to-cytoplasmic translocation of the mRNA-binding and -stabilizing protein HuR. However, the mechanism by which LFA-1 engagement controls HuR localization is not known. Here, we identify and characterize four key regulators of LFA-1-induced changes in HuR activity: the p38 pathway kinase MK2 and the constitutive nuclear proteins hnRNPs C, H1 and K. LFA-1 engagement results in rapid, sequential activation of p38 and MK2. Post-LFA-1 activation, MK2 inducibly associates with both hnRNPC and HuR, resulting in the dissociation of HuR from hnRNPs C, H1 and K. Freed from the three hnRNPs, HuR translocates from the nucleus to the cytoplasm, and mediates the stabilization of labile cytokine transcripts. Our results suggest that the modulation of T cell cytokine mRNA half-life is an intricate process that is negatively regulated by hnRNPs C, H1 and K and requires MK2 as a critical activator.

How We Got Smart: Improving Interdisciplinary Communication When Summoning Neonatology to High-Risk Deliveries.

Communication around high-risk deliveries is critical to ensure patient safety. A hospital-wide system change in paging the neonatal resuscitation team (NRT) to deliveries was implemented but disliked. An interdisciplinary team seized the opportunity to explore opportunities for an enhanced system to improve communication. The team designed a new screen to our smart panel (responder 5 staff terminal, Rauland, Mount Prospect, Illinois) to page NRT with the location and primary indication for which they were needed at delivery. Surveys assessed user satisfaction among labor and delivery and NRT. Before and after implementation of the smart panel, we assessed number of NRT pages, frequency of NRT being paged prior to the delivery, the time between page and delivery, and use of the code button to summon help. Labor and delivery and NRT user satisfaction greatly improved with the smart panel. Frequency of NRT being paged before birth increased with fewer code pages being used to summon NRT to deliveries. A touch screen-based notification system can enhance timely notification to summon NRT to deliveries while concurrently enhancing satisfaction of providers in both the delivery room and on the NRT.

How Do Obstetric and Neonatology Teams Communicate Prior to High-Risk Deliveries?

BACKGROUND: Improving communication in healthcare improves the quality of care and patient outcomes, but communication between obstetric and neonatal teams before and during a high-risk delivery is poorly studied. STUDY DESIGN: We developed a survey to study communication between obstetric and neonatal teams around the time of a high-risk delivery. We surveyed neonatologists from North America and asked them to answer questions about their institutions' communication practices. RESULTS: The survey answers revealed variations in communication practices between responders. Most institutions relied on nursing to communicate obstetric information to the neonatal team. Although a minority of institutions used a standardized communication process to summon neonatology team or to communicate in the delivery room, these reported higher rates of information sharing and greater satisfaction with communication between services. CONCLUSION: Standardized communication procedures are an underutilized method of communication and have the potential to improve communication around high-risk deliveries.

Identifying a quality improvement project.

An important step on the roadmap to a successful quality improvement (QI) project is careful selection of topics and aims to be addressed by QI projects. Using information from a variety of data monitoring systems as well as individual events and experiences, leaders of neonatal units and QI teams should first identify quality and safety gaps in their unit. They should then use an explicit, formal process for selecting the best projects to which their limited time and resources should be allocated. Priority should be given to projects that address a quality gap of high magnitude and impact, have a high likelihood of success, have a champion, fit with the unit's state of readiness for change, have organizational support and align with organizational priorities. The scope of the project should also match the experience and expertise of the QI team.

Eliminating Undesirable Variation in Neonatal Practice: Balancing Standardization and Customization.

Consistency of care and elimination of unnecessary and harmful variation are underemphasized aspects of health care quality. This article describes the prevalence and patterns of practice variation in health care and neonatology; discusses the potential role of standardization as a solution to eliminating wasteful and harmful practice variation, particularly when it is founded on principles of evidence-based medicine; and proposes ways to balance standardization and customization of practice to ultimately improve the quality of neonatal care.

Papillary fibroelastoma of the aortic valve presenting with chronic angina and acute stroke: a case report.

BACKGROUND: Papillary fibroelastomas are rare, benign cardiac tumors that are often found on cardiac valvular surfaces. Most are incidental discoveries during surgery or autopsy. The clinical presentation of fibroelastoma varies widely, ranging from clinically asymptomatic to severe thromboembolic events. CASE PRESENTATION: We report a case of 65-year-old white man diagnosed with scattered, bilateral acute cerebral hemisphere infarcts with a history of chronic angina. Transesophageal echocardiography identified a fibroelastoma on the right coronary cusp of the aortic leaflet. Cardiac catheterization revealed mild non-obstructive stenosis. We postulate that the etiology of his angina is related to the dynamic occlusion of his right coronary ostium by the fibroelastoma. CONCLUSIONS: To the best of our knowledge, this is the first case report describing a patient with a cardiac papillary fibroelastoma who presented with both chronic angina and acute stroke.