Evaluation of the effect of rozanolixizumab on pregnancy outcomes and pre- and postnatal development in cynomolgus monkeys.

Rozanolixizumab, a humanised immunoglobulin (Ig) G4 monoclonal antibody that selectively inhibits binding of IgG to the neonatal Fc receptor (FcRn), was evaluated in an embryo-foetal enhanced pre- and postnatal development (ePPND) study. Pregnant female cynomolgus monkeys (19 per group) received subcutaneous rozanolixizumab 50 mg/kg or 150 mg/kg or vehicle every 3 days from gestation day 20 until delivery. The proportion of pregnancy losses was 15.

Blood analytes of clinically normal and diseased neonatal and weaned farmed white-tailed deer () fawns.

Recent research focused on farmed deer has exposed many knowledge gaps regarding health assessment protocols for white-tailed deer (WTD). The objectives of this study were to establish de novo blood analyte reference intervals for farmed WTD fawns at birth (1-2 days of age;  = 84) and again at weaning (76-125 days of age;  = 28), to compare data at birth and at weaning to understand how these analytes are affected by the intrinsic factors age and sex in clinically normal WTD fawns, and to compare between clinically normal and sick WTD weanlings (respiratory disease  = 12; orbivirus-infected  = 6). Reference intervals were established for WTD fawns at birth and weaning.

The use of recovery animals in nonclinical safety assessment studies with monoclonal antibodies: further 3Rs opportunities remain.

Assessment of reversibility from nonclinical toxicity findings in animals with potential adverse clinical impact is required during pharmaceutical development, but there is flexibility around how and when this is performed and if recovery animals are necessary. For monoclonal antibodies (mAbs) and in accordance with ICH S6(R1) if inclusion of recovery animals is warranted, this need only occur in one study. Data on study designs for first-in-human (FIH)-enabling and later-development toxicity studies were shared from a recent collaboration between the NC3Rs, EPAA, Netherlands Medicines Evaluation Board (MEB) and 14 pharmaceutical companies.

Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach.

To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs.

Prospective trial of different antimicrobial treatment durations for presumptive canine urinary tract infections.

Background: Avoidance of unnecessary antimicrobial administration is a key tenet of antimicrobial stewardship; knowing the optimal duration of therapy obviates over-treatment. However, little research has been performed to establish course lengths for common canine infections. In clinical practice, antimicrobial therapy is frequently prescribed in dogs presenting lower urinary tract signs (haematuria, pollakiuria and dysuria/stranguria).

Review of the Technical, Toxicological, and PKPD Considerations for Conducting Inhalation Toxicity Studies on Biologic Pharmaceuticals-The Outcome of a Cross-Industry Working Group Survey.

The inhaled route is still a relatively novel route for delivering biologics and poses additional challenges to those encountered with inhaled small molecules, further complicating the design and interpretation of toxicology studies. A working group formed to summarize the current knowledge of inhaled biologics across industry and to analyze data collated from an anonymized cross-industry survey comprising 12 inhaled biologic case studies (18 individual inhalation toxicity studies on monoclonal antibodies, fragment antibodies, domain antibodies, oligonucleotides, and proteins/peptides). The output of this working group provides valuable insights into the issues faced when conducting toxicology studies with inhaled biologics, including common technical considerations on aerosol generation, use of young and sexually mature nonhuman primates, pharmacokinetic/pharmacodynamic modeling, exposure and immunogenicity assessment, maximum dose setting, and no observed adverse effect levels determination.

BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics.

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies.

Case Studies Discussing the Pathology, Immunogenicity, and Proposed Mechanism of Toxicity of an Inhaled Anti-TGFβ Humanized Fab Antibody in Non-Human Primates and Mice.

Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor β via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes.

Living la Vida T-LoCoH: site fidelity of Florida ranched and wild white-tailed deer () during the epizootic hemorrhagic disease virus (EHDV) transmission period.

Background: Epizootic hemorrhagic disease virus (EHDV) is a pathogen vectored by midges that causes significant economic loss in the cervid farming industry and affects wild deer as well. Despite this, its ecology is poorly understood. Studying movement and space use by ruminant hosts during the transmission season may elucidate EHDV ecology by identifying behaviors that can increase exposure risk.

Antibodies to Epizootic Hemorrhagic Disease Virus (EHDV) in Farmed and Wild Florida White-Tailed Deer ().

The transmission of multiple serotypes of epizootic hemorrhagic disease virus (EHDV) between farmed and free-ranging wildlife is of interest to livestock industries and natural resource agencies. We compared the seroprevalence of EHDV-1, -2, and -6 in wild and farmed white-tailed deer () herds in Florida, US. We compared serological prevalence, circulating serotypes, antibody titers, and viremia with the use of 171 whole-blood samples from 150 unvaccinated white-tailed deer from farm pens, a farm preserve, and wild deer on adjacent public lands between March 2016 and May 2017.

The impact of vector control on the prevalence of Theileria cervi in farmed Florida white-tailed deer, Odocoileus virginianus.

Background: Vector-borne diseases exert a global economic impact to the livestock industry. Understanding how agriculture practices and acaricide usage affect the ecology of these diseases is important for making informed management decisions. Theileria cervi is a hemoprotozoan parasite infecting white-tailed deer (Odocoileus virginianus) and is transmitted by the lone star tick, Amblyomma americanum.

CDOM-DOC relationship in contrasted coastal waters: implication for DOC retrieval from ocean color remote sensing observation.

Increasing our knowledge on dissolved organic carbon (DOC) spatio-temporal distribution in the coastal ocean represents a crucial challenge for better understanding the role of these ecosystems in the global oceanic carbon cycle. The assessment of DOC concentration from the absorption properties of the colored part of the dissolved organic matter (a(cdom)) was investigated from an extensive data set covering a variety of coastal environments. Our results confirmed that variation in the a(cdom)(412) to DOC ratio (a*(cdom)(412)) can be depicted from the CDOM spectral slope in the UV domain (S(275-295)).

Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children.

Proteinuria in canine patients with lymphoma.

Objectives: To determine if proteinuria is more common in dogs with lymphoma when compared with healthy dogs and to assess the severity and frequency of proteinuria in dogs with lymphoma.

Methods: Determination of urine protein:creatinine ratio in 32 dogs with lymphoma compared with 30 healthy dogs.

Results: Canine patients with lymphoma are more likely to be proteinuric compared with healthy dogs.

Long-term stability of bevacizumab repackaged in 1mL polypropylene syringes for intravitreal administration.

Introduction: The anti-angiogenic monoclonal antibody, bevacizumab, is currently used by intravitreal administration as off-label drug to treat age-related macular degeneration or other ophthalmologic diseases. For this purpose, commercial bevacizumab is repackaged in 1mL polypropylene syringes under sterile conditions. However, no complete study on the stability of this hospital-based preparation is available.

Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas.

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas.

Helodermin-loaded nanoparticles: characterization and transport across an in vitro model of the follicle-associated epithelium.

M cells represent a potential portal for oral delivery of peptides and proteins due to their high endocytosis abilities. An in vitro model of human FAE (co-cultures) was used to evaluate the influence of M cells on the transport of free and encapsulated helodermin--a model peptide--across the intestinal epithelium. M cells enhanced transport of intact helodermin (18-fold, Papp=3 x 10(-6) cm s(-1)).

Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site.

A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.

Treatment of canine Alopecia X with trilostane.

Sixteen Pomeranians and eight miniature poodles presenting with clinical signs of alopecia X, elevated blood concentrations of 17-hydroxyprogesterone post stimulation with adrenocorticotropic hormone and increased urinary cortisol/creatinine ratios were treated with trilostane, a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase. Trilostane was given once or twice daily at a mean dose of 10.85 mg kg(-1) day(-1).

The urinary corticoid:creatinine ratio (UCCR) in healthy cats undergoing hospitalisation.

Thirty-one healthy pet cats had voided urine samples collected prior to, during and after a brief period of hospitalisation. Urinary corticoids were measured, both prior to and following an extraction technique, and the urinary corticoid:creatinine ratio (UCCR) was calculated. Associations between the UCCR and age, sex, breed and time of urine collection were investigated.

Effect and mechanisms of the anti-prolactin drug cabergoline on pseudopregnancy in the bitch.

A potent anti-prolactin drug, cabergoline, administered orally for five days, was clinically successful in treating three different clinical manifestations of pseudopregnancy in referred bitches. The clinical conditions treated were categorised as standard pseudopregnant bitches (n = 8), those previously unsuccessfully treated with hormones (n = 10) and those which had behavioural pseudopregnancy following ovariohysterectomy (n = 8). The number of bitches whose owners reported a 'good' response was seven out of eight, six out of 10 and six out of eight, respectively.

Vaginal cysts causing tenesmus in a bitch.

An eight-year-old female border collie was referred with a two-month history of faecal tenesmus. Ultrasonography and radiology identified fluid-filled masses in the cranial vagina. The fluid was drained from the vaginal cysts via an episiotomy and the clinical signs resolved.