Momenta Pharmaceuticals (United States)

<p>Supplementary Table 1 lists proteins significantly altered by necuparanib treatment</p>

Summary:Approximately one-third of the world’s population suffers from allergies1. Allergen exposure crosslinks mast cell- and basophil-bound immunoglobulin E (IgE), triggering the release of inflammatory mediators, including histamine2. Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease3–5. It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or impact biological activity is completely unknown6. We therefore unbiasedly examined glycosylation patterns of total IgE from peanut-allergic and non-atopic individuals. This revealed an increase in sialic acid content on total IgE from peanut-allergic individuals compared to non-atopic subjects. Sialic acid removal from IgE attenuated effector cell degranulation and anaphylaxis in multiple functional models of allergic disease. Therapeutic interventions, including sialic acid removal from cell-bound IgE with a FcεRI targeted-neuraminidase, or administration of asialylated IgE, markedly reduced anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease.

<div class="section abstract"><div class="htmlview paragraph">Modeling retroreflective material in a three-dimensional computer modeling and Physically Based Rendering (PBR) engine is extremely difficult without fully understanding the physics behind how the light rays interact and behave with the retroreflective materials. Without the proper engineering and physics understanding, incorrect, inaccurate and unfair animations can be created that attempt to show the visibility of retroreflective materials. In this paper we will discuss the engineering and physics of retroreflective materials and how light interacts with these materials. We will also describe how to incorporate the engineering and science of retroreflective materials into a PBR engine to create a fair and accurate light simulation displaying the visibility of the retroreflective materials.</div></div>

Clostridium difficile infection (CDI) is the principal cause of nosocomial diarrhea and pseudomembranous colitis associated with antibiotic therapy. The pathological effects of CDI are primarily attributed to toxins A (TcdA) and B (TcdB). Adequate toxin-specific antibody responses are associated with asymptomatic carriage, whereas insufficient humoral responses are associated with recurrent CDI. While the data supporting the importance of anti-toxin antibodies are substantial, clarity about the toxin domain specificity of these antibodies is more limited. To investigate this matter, combinations of human mAbs targeting multiple domains of TcdB were assessed using toxin neutralization assays. These data revealed that a combination of mAbs specific to all major toxin domains had improved neutralizing potency when compared to equivalent concentrations of a single mAb or a combination of mAbs against one or two domains. The function and toxin domain binding specificity of serum antibodies elicited by immunization of hamsters with a toxoid vaccine candidate was also assessed. Immunization with a toxoid vaccine candidate provoked toxin neutralizing antibodies specific to multiple domains of both TcdA and TcdB. When assessed in a toxin neutralization assay, polyclonal sera displayed greater activity against elevated concentrations of toxins than equivalent concentrations of individual mAbs. These data suggest a potential benefit of any antibody based therapeutic or prophylactic treatment that targets multiple toxin domains.

Background & AimsThe occurrence of drug‐induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.MethodsAn initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins.ResultsWe observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid‐binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated.ConclusionsThese results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

With the rapid growth of recombinant monoclonal antibodies and intravenous immunoglobulin (IVIg) medicines, the understanding of human immunoglobulin G (IgG) subclasses becomes more necessary. It is essential to develop effective techniques and methodologies which have the capability for deep characterization. We have created an approach by applying LC and liquid chromatography-mass spectrometry (LC-MS) methods to thoroughly characterize Fc/2 sequence variants for human IgG subclasses in complex samples. Identification and relative quantitation of sequence variants have been provided. Unique glycan information of each IgG subclass can also be obtained by this method. The approach was based on high-resolution HPLC separation followed by intact LC-MS. Peptide mapping was performed following sample fractionation to identify sequence variants. IVIg, a purified IgG mixture from pooled human plasma of thousands of blood donors, was selected as an example for method development. The amino acid sequence variants in IgG Fc/2 constant region were fully investigated for all subclasses by these methods. A total of 19 sequence variants were identified, and their relative abundances were quantitated, which included six variants in IgG1, eight in IgG2, three in IgG3, and two in IgG4. Unique glycan data was also provided for each Fc subclass, which is particularly important for IgG3; glycans from this subclass have only previously been reported together with IgG2 or IgG4. The method described in this paper has been proved to be an effective approach for deep characterization of IgG Fc/2 for complex samples. The findings of IVIg from these studies are also valuable for better understanding of human IgGs.