Safety and Efficacy of Immune Globulins and Alpha-1 Proteinase Inhibitors

Principal Investigator: Dorothy Scott, MD
Office / Division / Lab: OBRR / DH / LPD

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Overview

Public Health Issue: The mission of FDA is to protect and enhance the public health. To accomplish these goals, it is important to be able to predict and evaluate the potency and safety of our plasma-derived products, Immune Globulins, Alpha-1 Proteinase Inhibitor (A1PI), and antivenoms and antitoxins. We are currently focused on (1) Animal models of disease that can be used to predict and test efficacy of counterterrorism IG products, (2) Correlates of immune globulin efficacy in prevention of existing and emerging infectious diseases such as influenza and measles, (3) Particulate and aggregate formation in IG products - detection and impact on product stability and safety, (4) A1PI deficiency disease pathogenesis and protease/antiprotease balance in the lung, with the goal of providing new data to inform A1PI therapy, and (5) A1PI aggregation and its role in disease and product potency.

Regulatory Contribution: Our research contributes to enhanced assurance of efficacy, safety, and tolerability of immune globulins and A1PI. Specifically, the regulatory contributions are: (1) developing better animal models and in vitro tests that can be used to predict efficacy of counterterrorism-directed and influenza-targeted IG products that cannot be studied in humans for efficacy; (2) enhanced problem-solving for products with particulate/aggregate issues; (3) understanding the role of A1PI in inflammation and infection, which informs dosing, route of administration, and clinical study design for A1PI therapy; and (4) identifying mechanisms of A1PI aggregation, which impacts product manufacturing, potency, testing, and is related to disease pathogenesis and novel therapies in patients with abnormal A1PI protein expression.

Research Approach: (1) Animal models and in vitro tests for IG product potency - our model of progressive vaccinia in SCID mice has been well-characterized with respect to clinical disease, clinical relevance to human disease, viral tropism, and response to VIGIV products. (2) Surface plasmon resonance is being evaluated as a sensitive detection method for influenza H5 hemagglutinin receptor binding. (3) Aggregates in products are being characterized by HPLC and light scattering techniques, and correlated with in vitro monocyte activation. (4) A1PI aggregates will be characterized and compared using atomic force microscopy to elucidate the structure of in-vivo and in-vitro generated polymers. (5) Regulated local (pulmonary) expression of A1PI and inflammatory mediators are being studied in secretions and pathology specimens from patients with A1PI deficiency, COPD, and acute respiratory infections.

Mission Relevance & Outcomes: These studies support our science-based evaluation of products with the goal of enhancing their efficacy, potency and safety. Outcomes to date have included: use of our progressive vaccinia model to support VIGIV licensure and to characterize investigational products; a defined regulatory pathway for changing measles potency specifications in IG products (presented at the Blood Products Advisory Committee 5/01/08); collaboration with WHO to characterize and make available the First WHO International Standard for A1PI; pending publication of a proposed model for A1PI polymerization; assessment of A1PI protein and activity in pulmonary specimens from infected and control subjects.

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Publications

J Infect Dis 2008 Dec 15;198(12):1783-1793
Macrophage Impairment Underlies Airway Occlusion in Primary Respiratory Syncytial Virus Bronchiolitis.
Reed JL, Brewah YA, Delaney T, Welliver T, Burwell T, Benjamin E, Kuta E, Kozhich A, McKinney L, Suzich J, Kiener PA, Avendano L, Velozo L, Humbles A, Welliver Sr RC, Coyle AJ

Clin Infect Dis 2008 May 15;46(10):1555-61
Severe eczema vaccinatum in a household contact of a smallpox vaccinee
Vora S, Damon I, Fulginiti V, Weber SG, Kahana M, Stein SL, Gerber SI, Garcia-Houchins S, Lederman E, Hruby D, Collins L, Scott D, Thompson K, Barson JV, Regnery R, Hughes C, Daum RS, Li Y, Zhao H, Smith S, Braden Z, Karem K, Olson V, Davidson W, Trindade G, Bolken T, Jordan R, Tien D, Marcinak J

J Virol 2007 Jul;81(14):7449-62
Temporal analysis of Andes virus and Sin Nombre virus infections of Syrian hamsters.
Wahl-Jensen V, Chapman J, Asher L, Fisher R, Zimmerman M, Larsen T, Hooper JW

Cancer Res 2007 May 15;67(10):5059
Regulatory B cells inhibit antitumor immunity.
Inoue S, Scott D, Golding B, Leitner WW

J Infect Dis 2006 Sep 15;194(6):781-9
Measles-virus-neutralizing antibodies in intravenous immunoglobulins.
Audet S, Virata-Theimer ML, Beeler JA, Scott DE, Frazier DJ, Mikolajczyk MG, Eller N, Chen FM, Yu MY

Cancer Res 2006 Aug 1;66(15):7741-7
Inhibitory effects of B cells on antitumor immunity.
Inoue S, Leitner WW, Golding B, Scott D

Curr Opin Biotechnol 2005 Oct;16(5):561-7
The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals.
Farshid M, Taffs RE, Scott D, Asher DM, Brorson.

Nat Med 2005 Jul;11(7):740-7
Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus.
Edghill-Smith Y, Golding H, Manischewitz J, King LR, Scott D, Bray M, Nalca A, Hooper JW, Whitehouse CA, Schmitz JE, Reimann KA, Franchini.

J Virol 2005 Jun;79(11):6791-800
Identification of a Linear Peptide Recognized by Monoclonal Antibody 2D7 Capable of Generating CCR5-Specific Antibodies with Human Immunodeficiency Virus-Neutralizing Activity.
Khurana S, Kennedy M, King LR, Golding.

Vaccine 2005 Feb 25;23(14):1730-8
Programming of CTL with heat-killed Brucella abortus and antigen allows soluble antigen alone to generate effective secondary CTL.
Inoue S, Golding B, Scott.

Clin Diagn Lab Immunol 2004 Nov;11(6):1158-64
Characterization of Antibodies to Capsular Polysaccharide Antigens of Haemophilus influenzae Type b and Streptococcus pneumoniae in Human Immune Globulin Intravenous Preparations.
Mikolajczyk MG, Concepcion NF, Wang T, Frazier D, Golding B, Frasch CE, Scott D.

J Med Primatol 2004 Aug;33(4):167-74
Systemic and mucosal immunity in rhesus macaques immunized with HIV-1 peptide and gp120 conjugated to Brucella abortus.
Eller N, Golding H, Inoue S, Beining P, Inman J, Matthews N, Scott DE, Golding.

Vox Sang 2004 Feb;86(2):125-9
Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.
Goldsmith JC, Eller N, Mikolajczyk M, Manischewitz J, Golding H, Scott DE.