Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo.

There are no approved drug therapies that can prevent or slow the progression of Parkinson's disease (PD). Accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in PD. α-Synuclein is a core component of Lewy bodies and neurites that neuropathologically define PD, suggesting that α-synuclein may be a key causative agent in PD.

A QSP Model for Predicting Clinical Responses to Monotherapy, Combination and Sequential Therapy Following CTLA-4, PD-1, and PD-L1 Checkpoint Blockade.

Over the past decade, several immunotherapies have been approved for the treatment of melanoma. The most prominent of these are the immune checkpoint inhibitors, which are antibodies that block the inhibitory effects on the immune system by checkpoint receptors, such as CTLA-4, PD-1 and PD-L1. Preclinically, blocking these receptors has led to increased activation and proliferation of effector cells following stimulation and antigen recognition, and subsequently, more effective elimination of cancer cells.

Prognostic Significance of Liver Metastasis in Durvalumab-Treated Lung Cancer Patients.

Introduction: Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic non-small-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks.

Patients And Methods: A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status.

Results: In all, 569 patients were included.

A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer.

Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters.

Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC.

Introduction: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).

Methods: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity.

simulation of a clinical trial with anti-CTLA-4 and anti-PD-L1 immunotherapies in metastatic breast cancer using a systems pharmacology model.

The low response rate of immune checkpoint blockade in breast cancer has highlighted the need for predictive biomarkers to identify responders. While a number of clinical trials are ongoing, testing all possible combinations is not feasible. In this study, a quantitative systems pharmacology model is built to integrate immune-cancer cell interactions in patients with breast cancer, including central, peripheral, tumour-draining lymph node (TDLN) and tumour compartments.

Detecting bliss synergy in in vivo combination studies with a tumor kinetic model.

Linear models are generally reliable methods for analyzing tumor growth in vivo, with drug effectiveness being represented by the steepness of the regression slope. With immunotherapy, however, not all tumor growth follows a linear pattern, even after log transformation. Tumor kinetics models are mechanistic models that describe tumor proliferation and tumor killing macroscopically, through a set of differential equations.

Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status.

Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS.

Nullifying phosphatidic acid effect and controlling phospholipase D associated browning in litchi pericarp through combinatorial application of hexanal and inositol.

The role of phospholipid modification initiated by phospholipase D (PLD) in enzymatic browning has been revoked through this study. Various alcohols and aldehydes were tried to read out their PLD controlling behaviour. Based on in-vitro results, reagents like hexanal and inositol were used to regulate PLD activity of litchi fruit stored at ambient temperature and their effects on fruit quality and physiological characteristics were also investigated.

MEDI3039, a novel highly potent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 agonist, causes regression of orthotopic tumors and inhibits outgrowth of metastatic triple-negative breast cancer.

Background: TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists are attractive anti-tumor agents because of their capability to induce apoptosis in cancer cells by activating death receptors (DR) 4 and 5 with little toxicity against normal cells. Despite an attractive mechanism of action, previous clinical efforts to use TRAIL receptor agonists have been unsuccessful. In this study, we examined MEDI3039, a highly potent multivalent DR5 agonist, in breast cancer cell lines and in vivo models.

Sustainable Development Goals: Leveraging the Global Agenda for Driving Health Policy Reforms and Achieving Universal Health Coverage in India.

Universal Health Coverage (UHC) is now the critical yardstick for countries to measure and track progress toward the "Sustainable Development Goals (SDGs)." Being a signatory, India has started taking measures to attain the targets laid out within the SDG framework and achieving the UHC. With India's National Health Policy (NHP) - 2017 in place, the policy environment for transforming country's health landscape coincides with that of the global approach toward strengthening of health systems and achieving UHC.

Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status.

The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two-compartment model with both linear and nonlinear clearances.

Population Modeling of Tumor Kinetics and Overall Survival to Identify Prognostic and Predictive Biomarkers of Efficacy for Durvalumab in Patients With Urothelial Carcinoma.

Durvalumab is an anti-PD-L1 monoclonal antibody approved for patients with locally advanced or metastatic urothelial carcinoma (UC) that has progressed after platinum-containing chemotherapy. A population tumor kinetic model, coupled with dropout and survival models, was developed to describe longitudinal tumor size data and predict overall survival in UC patients treated with durvalumab (NCT01693562) and to identify prognostic and predictive biomarkers of clinical outcomes. Model-based covariate analysis identified liver metastasis as the most influential factor for tumor growth and immune-cell PD-L1 expression and baseline tumor burden as predictive factors for tumor killing.

A computational multiscale agent-based model for simulating spatio-temporal tumour immune response to PD1 and PDL1 inhibition.

When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy.

Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody, in patients with recurrent glioblastoma.

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity.

Inactivation thermodynamics and iso-kinetic profiling for evaluating operational suitability of milk clotting enzyme immobilized in composite polymer matrix.

Milk clotting enzyme (MCE) was immobilized in alginate-pectate interwoven gel with the yield of 73%. The encapsulated enzyme retained most of the protein load while soluble enzyme lost major proportion of activity after few hours. The immobilized enzyme showed high operational stability by retaining 40% activity even after 10 uses.

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.

Background: PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC).

Development of Immunoassays for the Quantitative Assessment of Amyloid-β in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies.

Utilizing decision making biomarkers in drug development requires thorough assay validation. Special considerations need to be taken into account when monitoring biomarkers using immunoassays in the presence of therapeutic antibodies. We have developed robust and sensitive assays to assess target engagement and proof of mechanism to support the clinical progression of a human monoclonal antibody against the neurotoxic amyloid-β (Aβ)42 peptide.

Combinatorial approaches for controlling pericarp browning in Litchi (Litchi chinensis) fruit.

The availability of fruit like litchi has been limited by variability in yield, alternate bearing, seasonal differences and most commonly post harvest problems. The litchi fruit has a very short shelf-life during which red color turns brown which greatly affects the appeal to consumer although not the unique flavor. This review article focuses on the post harvest problems especially browning of litchi.

A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors.

Purpose: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors.

Methods: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.

Preterm birth-associated neurodevelopmental impairment estimates at regional and global levels for 2010.

Background: In 2010, there were an estimated 15 million preterm births worldwide (<37 wk gestation). Survivors are at risk of adverse outcomes, and burden estimation at global and regional levels is critical for priority setting.

Methods: Systematic reviews and meta-analyses were undertaken to estimate the risk of long-term neurodevelopmental impairment for surviving preterm babies according to the level of care.

Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.

Alzheimer's disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-β in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-β are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby reducing formation of plaques predominantly composed of insoluble amyloid-β; the so-called peripheral sink hypothesis.

Population pharmacokinetics of sifalimumab, an investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus.

Background And Objectives: Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-α. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT)-based dosing regimens.

Has the Rate of Reduction in Infant Mortality Increased in India Since the Launch of National Rural Health Mission? Analysis of Time Trends 2000-2009 with Projection to 2015.

Objectives: National Rural Health Mission (NRHM) - India was launched in 2005 to tackle urban-rural health inequalities, especially in maternal and child health. We examined national and state level trends in Infant Mortality Rates (IMR) from 2000 through 2009 to: 1) assess whether the NRHM had increased the average annual reduction rate (AARR) of IMR 2) evaluate state-wise progress towards Millennium Development Goals (MDG4) and estimate required AARRs for 'off track' states.

Methods: Log-linear regression models were applied to national and state IMR data collated from the Sample Registration System (SRS)-India to estimate average annual reduction rates and compare AAARs before and after introduction of NRHM.

National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.

Background: Preterm birth is the second largest direct cause of child deaths in children younger than 5 years. Yet, data regarding preterm birth (<37 completed weeks of gestation) are not routinely collected by UN agencies, and no systematic country estimates nor time trend analyses have been done. We report worldwide, regional, and national estimates of preterm birth rates for 184 countries in 2010 with time trends for selected countries, and provide a quantitative assessment of the uncertainty surrounding these estimates.