On March 31, 2016 Atreca, Inc., a biotechnology company focused on developing novel therapeutics based on a deep understanding of the human immune response, reported positive preclinical findings generated using the Company’s Immune Repertoire Capture technology, presented at the Gordon Research Conference: Antibody Biology & Engineering, which took place in Galveston, TX, March 20-25, 2016 (Press release, Atreca, MAR 31, 2016, View Source [SID1234522967]). In a poster titled, "Protective Anti-Malarial Human Antibodies identified from P. falciparum CSP Immunized Kymice using Immune Repertoire Capture (IRC)", a research team including scientists at Atreca and collaborators at leading institutions reported key preclinical research findings, including:

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Atreca’s Immune Repertoire Capture technology applied in combination with Kymab’s Kymice, an Ig-gene humanized mouse platform, identified and generated potent antibodies comprised of human variable genes.
•Atreca identified diverse lineages (or families) of antibodies that bind to a key target, the circumsporozoite protein (CSP) of P. falciparum. Two of these lineages provided potent protection in an in vivo malaria-challenge model, resulting in >99% reduction of liver-stage parasite load.
Daniel Emerling, Ph.D., Atreca’s Senior Vice President, Research, stated, "IRC enabled identification of multiple lineages containing potent, anti-malarial human antibodies generated by activated mouse B cells. The diversified antibody library that we generated had a high hit rate of binding against the CSP target (34%). Our analyses also provide the foundation for understanding structure-activity relationships that mediate the binding of the antibodies that are efficacious in vivo. Furthermore, we have identified many other antibody sequences in these and other lineages that are highly similar to the efficacious antibodies and may therefore also be active in vivo."

Dr. Emerling continued, "We are grateful to both the Bill & Melinda Gates Foundation and the PATH Malaria Vaccine Initiative for supporting this critical research."

"These results disclosed at the Gordon Conference demonstrate the ability of Atreca’s Immune Repertoire Capture technology to generate novel antibodies with high in vivo potency from immune responses, as well as multiple lineages containing such antibodies," commented Tito A. Serafini, Ph.D., Atreca’s President, Chief Executive Officer, and Co-Founder. "While our primary focus continues to be on cancer immunotherapy, our IRC technology allows us to mine the key phenomenon driving efficacious immune responses in humans and animals in diverse disease settings, including infectious and autoimmune diseases."

Atreca recently reported use of its Immune Repertoire Capture technology to analyze the successful anti-tumor responses in individuals with non-progressing lung adenocarcinoma. Based on this and related research, select antibodies discovered by Atreca have progressed to preclinical testing in in vivo models of cancer, with the goal of selecting candidates to enter into more advanced preclinical studies.

The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

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Spine stereotactic body radiation therapy (SBRT) requires highly accurate positioning. We report our experience with markerless template matching and triangulation of kilovoltage images routinely acquired during spine SBRT, to determine spine position.
Kilovoltage images, continuously acquired at 7, 11 or 15 frames/s during volumetric modulated spine SBRT of 18 patients, consisting of 93 fluoroscopy datasets (1 dataset/arc), were analyzed off-line. Four patients were immobilized in a head/neck mask, 14 had no immobilization. Two-dimensional (2D) templates were created for each gantry angle from planning computed tomography data and registered to prefiltered kilovoltage images to determine 2D shifts between actual and planned spine position. Registrations were considered valid if the normalized cross correlation score was ≥0.15. Multiple registrations were triangulated to determine 3D position. For each spine position dataset, average positional offset and standard deviation were calculated. To verify the accuracy and precision of the technique, mean positional offset and standard deviation for twenty stationary phantom datasets with different baseline shifts were measured.
For the phantom, average standard deviations were 0.18 mm for left-right (LR), 0.17 mm for superior-inferior (SI), and 0.23 mm for the anterior-posterior (AP) direction. Maximum difference in average detected and applied shift was 0.09 mm. For the 93 clinical datasets, the percentage of valid matched frames was, on average, 90.7% (range: 49.9-96.1%) per dataset. Average standard deviations for all datasets were 0.28, 0.19, and 0.28 mm for LR, SI, and AP, respectively. Spine position offsets were, on average, -0.05 (range: -1.58 to 2.18), -0.04 (range: -3.56 to 0.82), and -0.03 mm (range: -1.16 to 1.51), respectively. Average positional deviation was <1 mm in all directions in 92% of the arcs.
Template matching and triangulation using kilovoltage images acquired during irradiation allows spine position detection with submillimeter accuracy at subsecond intervals. Although the majority of patients were not immobilized, most vertebrae were stable at the sub-mm level during spine SBRT delivery.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Background In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). Methods In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. Results Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. Conclusions In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044 .).

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VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.
VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.
Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).
VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

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