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August 2016 - Issue 8
Welcome to Battelle’s Life Sciences Research CRO+ Today Newsletter. The Battelle Life Sciences Research team provides fast, accurate answers for discovery, safety and efficacy with our integrated scientific and technological capabilities, world-class facilities and ability to meet technical, development and regulatory needs. Battelle Life Sciences CRO+ Today will keep you up-to-date on cutting-edge life sciences research.
When and where will the next flu pandemic emerge? Battelle is working with the Centers for Disease Control and Prevention (CDC) to develop point-of-care (POC) assays to track the spread of emerging strains of influenza.
As part of efforts that began in 2011, researchers at Battelle have developed a POC kit to be used for influenza serosurveillance. The multiplex assay gives public health officials on the ground a fast, easy and convenient way to test blood samples for exposure to several strains of flu with a single test. “Point-of-care assays are needed to give public health officials rapid results in the field without the need of advanced lab equipment or refrigeration,” explains Kim Weber, a Research Scientist on Battelle’s Bioassay team.
Battelle’s Rapid Influenza Immunity Test (RIIT) is a multiplex lateral flow assay that gives results in just 30 minutes with no specialized equipment. It is cost effective to deploy and can be easily transported and stored by public health officials working in developing nations.
The most recent version of the RIIT assay detects biomarkers of immune response to eight different strains of flu, including H1, H3, H5, H7 and H9 strains. The 8-plex assay builds on previous 5-plex and 10-plex versions, with strains selected to meet the CDC’s current needs for flu biosurveillance. A previous version of the assay has already been used to monitor serum levels of flu antigens in poultry workers in Bangladesh, a potential “hot spot” for emergence of an avian flu epidemic.
Monitoring immune response to influenza at the population level allows CDC and their international partners to identify new strains with epidemic or pandemic potential and put countermeasures in place to slow or stop their spread.
The rapid mutation of the flu virus makes assay development challenging. Immunity to common seasonal variants of flu can cause false positives for the strains under surveillance, potentially masking the emergence of dangerous new strains. Battelle researchers developed a process to remove antibodies for seasonal flu variants prior to testing to avoid interference and minimize false positives. They also worked on methods to stabilize the assay for field deployment.
Battelle plans to continue to develop new multiplex assays to support influenza surveillance. Continued development will be needed to adapt the assay to detect new and emerging strains of flu as they evolve. Researchers are also developing a companion high-throughput version of the assay for use in the lab.
Battelle has long supported influenza research for CDC. The Battelle bioassay team also has broad experience in developing and validating assays for detection of a wide variety of other biomarkers and analytes. Battelle offers comprehensive assay development and validation services for GLP drug development, pre-clinical and clinical research, diagnostics, vaccine efficacy and disease surveillance.
The Functional Observational Battery (FOB) has long been used with rodents as an initial screening device to assess the neurotoxic potential of candidate drugs and environmental toxins. However, large animals may be more appropriate models for certain drug classes. Battelle has modified the standard rodent FOB protocol for use with large animal models in cases where rodents do not provide suitable data. The modified FOBs were designed for use in large animal models.
The rodent version of the FOB has been used for decades for neurobehavioral testing and rapid neurotoxicity screening for candidate drugs. The standard battery consists of 40+ tests to assess central nervous system (CNS) and peripheral nervous system (PNS) effects including excitability, neuromuscular coordination, general activity, posture, grip strength, presence of tremors or convulsions, autonomic nervous system function, spontaneous activity, motor activity, arousal, sensory/motor reflex responses and body temperature. The battery includes observations under home cage, open field and handling conditions.
Modifying the FOB for use in large animals requires a deep understanding of the variations in the physiology, behavior and psychology of each species. For example, grip tests appropriate for rats cannot be directly translated to large animals whose extremities are not made for gripping. Similarly, standards for normal and stressed behavior under open field conditions for rats,a prey species, are very different from those in larger animals of a predator species. In some cases, standard rodent tests are simply not practical or feasible for larger species; “open field” conditions for NHPs are difficult to create in a lab environment.
Battelle researchers analyzed the 40+ tests in the standard rodent FOB and developed a set of modified tests, procedures and evaluation standards appropriate for two large species. They then characterized and developed a series of home cage and open field tests for rapid CNS screening in rats and the two large animal species. All three were tested using the FOB under a sedative and a stimulant. Researchers were able to then compare the behavioral and CNS effects on the different species at different dosages. The study showed that FOB data in both species can discriminate between the behavioral effects of stimulant and sedative drug treatments. Furthermore, these findings are consistent with behavioral effects demonstrated in the rodent model.
The FOB studies were part of internal research conducted at Battelle in order to expand the services we are able to offer our clients. As a nonprofit, mission-driven research organization, Battelle continually reinvests in internal research studies to advance our understanding of critical problems faced by the research community.
Battelle is also working to develop new methods to collect neurobehavioral and cardiovascular data simultaneously. By expanding the scope of data collected during a single study, we can achieve the very important goal of reducing the overall number of animals used for safety pharmacology and environmental toxicology studies. Researchers will share results from recent validation studies in an upcoming issue of Battelle CRO+ Today and at the fall conferences for the Safety Pharmacology Society and the Society for Neuroscience.
Battelle has been awarded a five-year, Indefinite Delivery/Indefinite Quantity (IDIQ) contract, with a potential value of $19 million, by the National Cancer Institute (NCI). Under the Preclinical Toxicology of Drugs Developed for Cancer Patients contract, Battelle will bid for task orders to support NCI’s program to develop and advance emerging cancer therapeutics to clinical trials.
The goal of the NCI program is to evaluate new drugs intended for the treatment of cancer. Battelle will be working directly with NCI to perform toxicology studies for a variety of drug candidates, including both small molecules and biologics. Data gathered from studies conducted under the contract may serve as the basis for filing for an IND (investigational new drug) application. MaryEllen Lynch, the Battelle Program Manager for the contract, explains, “Battelle has collaborated successfully with NCI for nearly 30 years. We have an experienced, full-service toxicology and safety pharmacology assessment team standing ready to help NCI get products through required preclinical studies and into the clinics where they are needed.”
The 2016 IDIQ is one of many awarded to Battelle by NCI since 1980. Over the years, researchers at Battelle have conducted numerous toxicology studies for cancer therapeutics. Under this new contract, Battelle may provide NCI with a full spectrum of services, including:
Battelle has been conducting preclinical drug development programs for global regulatory submissions for the pharmaceutical industry and the government for more than 35 years. In the past five years, the Battelle toxicology team has successfully conducted more than 1,000 relevant studies supporting preclinical development, including safety pharmacology, analytical and bioanalytical method development and validation, efficacy animal model development, efficacy studies, validation and analysis of biomarkers, and Good Laboratory Practices (GLP) and non-GLP toxicology in multiple species and in multiple routes of administration.
The NCI is the federal government's principal agency for cancer research and training. It is part of the National Institutes of Health (NIH), under the Department of Health and Human Services (HHS). Originally established under the National Cancer Institute Act of 1937, NCI now coordinates the National Cancer Program, which conducts and supports research, training, health communications, and other programs related to the diagnosis, prevention and treatment of cancer.
Battelle is pleased to continue support for NCI’s mission to bring new cancer treatments to clinics and cancer patients.
Researchers at Battelle contributed to two new papers detailing results from animal efficacy studies of a new treatment for inhalational anthrax. The papers have been accepted for publication by the journal Antimicrobial Agents and Chemotherapy.
The papers describe results of animal efficacy studies conducted by Battelle under the FDA animal rule for licensure of Elusys Therapeutics’ ANTHIM (obiltoxaximab) Injection, which received FDA approval in March 2016. ANTHIM acts as a treatment or prophylactic for inhalational anthrax. It neutralizes the effect of the anthrax toxin, preventing spread of the toxin throughout the body and the resulting tissue damage, which usually leads to death without treatment. It is expected to be an important addition to the Strategic National Stockpile (SNS), which stores large quantities of medicines, therapies and vaccines to protect the public in the case of an epidemic, natural disaster or terrorist attack.
Battelle scientists Drs. Daniel Sanford, Lisa N. Henning and Gregory V. Stark contributed to both the research and the papers. The first, “Obiltoxaximab for Inhalational Anthrax: Efficacy Projection Across a Range of Disease Severity,” focuses on the efficacy of obiltoxaximab for treatment of inhalational anthrax. The second, “Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Post-Exposure Prophylaxis in Animal Models of Inhalational Anthrax,” focuses on the prophylactic efficacy of the drug, both pre-exposure and post-exposure. Both studies used animal models under the FDA Animal Rule, which provides an alternative licensure pathway for products that cannot be practically or ethically tested in humans.
Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r2 = 0.86, P < 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.)
Read the entire paper in the April, 2016 edition of Clinical and Vaccine Immunology.
Battelle is pleased to welcome Dr. Satheesh Anand as the new Manager for Safety Assessment and Study Management for the Battelle Toxicology Team. Read More