Juvaris BioTherapeutics (United States)

Abstract Review: 91 refs.

CD98 is expressed on several tissue types and specifically upregulated on fast‐cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98‐specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell‐line derived xenograft models and was as efficacious as standard of care carboplatin in patient‐derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase‐3 and ‐7‐mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.

Best-in-class systems have evolved among alpha-1 antitrypsin (AAT) producers, specialty pharmacies and the Alpha-1 Foundation and AlphaNet patient groups. The Genetic Alliance, NORD and other independent parties have recognized the benefits regarding public policy, patient advocacy, medical research, medication adherence, patient identification and health outcomes. Driving the next quantum leap in disease state management for Alpha-1 patients will require strong leadership from both industry and patient groups. Six initiatives are suggested that will sustain best-in-class approaches to identify, treat and even cure Alpha-1 patients.

Abstract The decline in immunity in older adult humans results in a reduction of influenza vaccine efficacy. Elderly macaques (> 18 years old) have similar declines in immunity as indicated by significantly lower levels of circulating naïve CD4+ T cells, naïve CD8+ T cells and B cells and declines in pDC function compared to juvenile monkeys. To determine if the adjuvant activity of JVRS-100 can improve the efficacy of the inactivated influenza vaccine, Fluzone®, elderly monkeys were immunized with Fluzone® with or without JVRS-100 and challenged with a human seasonal influenza isolate, A/Memphis/7/2001 (H1N1). On the day of challenge, Fluzone®+JVRS-100 immunized animals had significantly higher plasma anti-influenza IgG (p<0.04) and IgA (p<0.01) titers than the un-adjuvanted immunized monkeys. After virus challenge, only the Fluzone®+JVRS-100 immunized animals had a significantly lower level of virus replication (p<0.05) relative to the unimmunized control animals. There were significant inverse correlations between peak influenza virus replication levels in the respiratory tract and plasma and tracheal anti-influenza IgG and IgA antibody titers prior to challenge. These results demonstrate that JVRS-100 enhances the immunogenicity and efficacy of a licensed inactivated influenza vaccine in an immunosenescent elderly monkey population.

Low levels of antithrombin (AT) have been independently associated with prolonged intensive care unit stay and an increased incidence of neurologic and thromboembolic events after cardiac surgery. We hypothesized that perioperative AT activity is independently associated with postoperative major adverse cardiac events (MACEs) in patients undergoing coronary artery bypass graft (CABG) surgery. We prospectively studied 1403 patients undergoing primary CABG surgery with cardiopulmonary bypass (CPB) (http://clinicaltrials.gov/show/NCT00281164). The primary clinical end point was occurrence of MACE, defined as a composite outcome of any one or more of the following: postoperative death, reoperation for coronary graft occlusion, myocardial infarction, stroke, pulmonary embolism, or cardiac arrest until first hospital discharge. Plasma AT activity was measured before surgery, after post-CPB protamine, and on postoperative days (PODs) 1-5. Multivariate logistic regression modeling was performed to estimate the independent effect of perioperative AT activity upon MACE. MACE occurred in 146 patients (10.4%), consisting of postoperative mortality (n = 12), myocardial infarction (n = 108), stroke (n = 17), pulmonary embolism (n = 8), cardiac arrest (n = 16), or a subsequent postoperative or catheter-based treatment for graft occlusion (n = 6). AT activity at baseline did not differ between patients with (0.91 ± 0.13 IU/mL; n = 146) and without (0.92 ± 0.13 IU/mL; n = 1257) (P = 0.18) MACE. AT activity in both groups was markedly reduced immediately after CPB and recovered to baseline values over the ensuing 5 PODs. Postoperative AT activity was significantly lower in patients with MACE than those without MACE. After adjustment for clinical predictors of MACE, AT activity on PODs 2 and 3 was associated with MACE. Preoperative AT activity is not associated with MACE after CABG surgery. MACE is independently associated with postoperative AT activity but only at time points occurring predominantly after the MACE.

The gastrointestinal tract (GIT) constitutes one of the largest immunological organs of the body. The GIT must permit absorption of nutrients while also maintaining the ability to respond appropriately to a diverse milieu of dietary and microbial antigenic components. Because of the diverse population of antigenic components within the GIT, a sophisticated mucosal immune system has evolved that relies on collaboration between the innate and adaptive arms of immunity. The collaborative, mucosal immune effort offers protection from harmful pathogens while also being tolerant of dietary antigens and normal microbial flora. Knowledge with respect to porcine mucosal immunity is important as we strive to understand the interrelationships among GIT physiology, immunology, and the resident microbiota. The aim of this review is to provide a descriptive overview of GIT immunity and components of the mucosal immune system and to highlight differences that exist between the porcine species and other mammals.

Cationic liposome‐DNA complexes formed with plasmid DNA (CLDC), CpG‐free plasmid DNA, or CpG‐containing oligodeoxynucleotides (ODN) were evaluated for their ability to elicit protective immunity against Punta Toro virus (PTV) challenge in the hamster infection model. Liposome‐DNA formulations were administered by the intraperitoneal route 4 h prior to inoculation of a highly lethal PTV inoculum. Survival outcomes, as well as reduction of viral burden and liver disease, were assessed. A dose of CLDC containing 30 μg of plasmid significantly improved survival outcome, decreased systemic and liver viral loads, and reduced liver pathology compared to animals receiving placebo. Known mouse‐ and human‐reactive ODNs delivered in liposome complexes failed to protect challenged hamsters. Treatment with liposomes containing non‐CpG motif‐containing plasmid reduced liver virus titers compared with untreated or CpG treated, but did not protect hamsters from death. This suggests that while elements other than CpG motifs may stimulate a response sufficient to control viral replication in the target organ, the empty vector plasmid DNA backbone with CpG islands appears to be critical to stimulating protection against mortality in the PTV hamster model. Supported by contract grant NO1‐AI‐15435 from the Virology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health.