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Gaithersburg, United States

The formulation development of monoclonal antibodies is extremely challenging, due to the diversity and complexity contained within this class of molecules. The physical and chemical properties of a monoclonal antibody dictate the behavior of the protein drug during manufacturing, storage and clinical administration. In the past few years, the use of high throughput technologies has been widely adapted to delineate unique properties of individual immunoglobulin Gs (IgGs) important for their development. Numerous screening techniques have been designed to reveal physical and chemical characteristics of a protein relevant to stability under production, formulation and delivery conditions. In addition, protein stability under accelerated stresses has been utilized to predict long-term storage behavior for monoclonal antibodies in the formulation. In this review, we summarize the recent advancements in the field of biophysical technology, with a specific focus on the techniques that can be directly applied to the formulation development of monoclonal antibodies. Several case studies are also presented here to provide examples of combining existing biophysical methods with high throughput screening technology in the formulation development of monoclonal antibody drugs. © 2012 American Chemical Society.

Rouet R.,Garvan Institute of Medical Research | Lowe D.,MedImmune | Christ D.,Garvan Institute of Medical Research | Christ D.,University of New South Wales
FEBS Letters | Year: 2014

Human monoclonal antibodies often display limited thermodynamic and colloidal stabilities. This behavior hinders their production, and places limitations on the development of novel formulation conditions and therapeutic applications. Antibodies are highly diverse molecules, with much of the sequence variation observed within variable domain families and, in particular, their complementarity determining regions. This has complicated the development of comprehensive strategies for the stability engineering of the human antibody repertoire. Here we provide an overview of the field, and discuss recent advances in the development of robust and aggregation resistant antibody therapeutics. © 2013 Published by Elsevier B.V. on behalf of Federation of European Biochemical Society. All rights reserved.

Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus (HAV; a picornavirus) and Hepatitis C virus (HCV; a flavivirus) two single strand plus-sense RNA viruses, in particular, have been found to use exosomes for viral transmission thus evading antibody-mediated immune responses. Paradoxically, both viral exosomes can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production. This article will review recent findings regarding these two viruses and outline how exosomes are involved in their transmission and immune sensing. © 2015, by the author; licensee MDPI, Basel, Switzerland.

McCafferty J.,IONTAS Ltd. | Schofield D.,MedImmune
Current Opinion in Chemical Biology | Year: 2015

The use of large genetically encoded binder libraries in co-operation with display technologies has matured over the past 25 years, and is now one of the primary methods used for selection of protein binders. Display technology has proven to be a robust and versatile method for generating binders to almost any antigen of interest. The evolution of this technology beyond antibody phage display has opened up new aspects for the concept of designer biologics. The ability to construct large populations of eukaryotic cells, including mammalian cells, where each cell expresses an individual antibody, peptide or engineered protein has added great value in identifying binders with desired properties. Here we review the evolution of display technology and highlight how it is being used today to generate binders with exquisite specificity, selectivity, affinity and developability characteristics. © 2015 .

Barlow J.L.,University of Cambridge | Bellosi A.,University of Cambridge | Hardman C.S.,University of Cambridge | Drynan L.F.,University of Cambridge | And 3 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: IL-4, IL-5, and IL-13 are thought to be central to the allergic asthmatic response. Previous work supposed that the essential source of these cytokines was CD4 + T H2 cells. However, more recent studies have suggested that other innate production of type 2 cytokines might be as important. Objectives: Nuocytes are a novel population of IL-13-producing innate cells, which are critical for protective immunity in Nippostrongylus brasiliensis infection. Given this, we investigated the potential existence and functional importance of nuocytes in experimental allergic asthma. Methods: We generated Il4 +/eGFPIl13 +/Tomato dual-reporter mice to study cytokine-producing cells during allergic inflammation. We adoptively transferred innate IL-13-producing cells to investigate their role in airways hyperreactivity (AHR). Results: We show that allergen-induced nuocytes infiltrate the lung and are a major innate source of IL-13. CD4 + T cells in the lung almost exclusively express only IL-13, whereas IL-4-producing T cells were restricted to the draining lymph nodes. Intranasal administration of IL-25 or IL-33 induced IL-13-producing nuocytes in the BAL fluid. Strikingly, adoptive transfer of wild-type nuocytes, but not Il13 -/- nuocytes, into Il13 -/- mice, which are normally resistant to IL-25-induced AHR, restored airways resistance and lung cell infiltration. Conclusions: These findings identify nuocytes as a novel cell type in allergic lung inflammation and an innate source of IL-13 that can directly induce AHR in the absence of IL-13-producing CD4 + T cells. These data highlight nuocytes as an important new consideration in the development of future allergic asthma therapy. © 2011 American Academy of Allergy, Asthma & Immunology.

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