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SAN DIEGO, CA, United States

Patent
Nexbio, Inc. | Date: 2010-08-23

The present invention provides new compositions and methods for preventing and treating pathogen infection. In particular, the present invention provides compounds having an anchoring domain that anchors the compound to the surface of a target cell, and a therapeutic domain that can act extracellularly to prevent infection of a target cell by a pathogen, such as a virus. The present invention also comprises therapeutic compositions having sialidase activity, including protein-based compounds having sialidase catalytic domains. Compounds of the invention can be used for treating or preventing pathogen infection, and for treating and reducing allergic and inflammatory responses. The invention also provides compositions and methods for enhancing transduction of target cells by recombinant viruses. Such compositions and methods can be used in gene therapy.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 6.00M | Year: 2005

DESCRIPTION (provided by applicant): Influenza is characterized by recurrent annual epidemics and periodic major worldwide pandemics. Because of the high disease-related morbidity and mortality, direct and indirect socio-economic impacts of influenza are enormous. In the last 100 years, there have been 3 major influenza pandemics. It has been about thirty years since the last pandemic. A new pandemic is considered imminent and one of the biggest challenges facing public health systems today. With recent technical progress, it has also become possible for bio-terrorists to create potential pandemic viral strains faster than natural evolution of the viruses. Therefore, a broad-spectrum therapeutic/prophylactic product for influenza is critically needed. We have identified a drug lead, Fludase(tm), which targets on all strains and subtypes of influenza including the potential pandemic strains. With the funding from a Phase I Biodefense SBIR application, we have demonstrated its efficacy against a variety of influenza viruses. Unlike the currently available Flu vaccines, Fludase(tm) does not need to be updated yearly. Fludase(tm) can be produced cost effectively and can be readily available at the onset of a natural pandemic or bio-warfare, and for annual epidemics. As a protein-based therapeutic agent administered topically and locally, Fludase(tm) can also potentially avoid the side effects and the risk of generating drug resistant viruses associated with the currently available expensive antiviral compounds. The objective of this grant application is to complete all necessary pre-clinical development and to initiate early stage clinical development of Fludase(tm).


The present invention provides a method of reducing the quanitity of mucus in the respiratory tract of a subject with elevated levels of mucus in said respiratory tract. The method includes administering to the subject a compound or composition containing a therapeutically effective amount of a fusion protein comprising a sialidase or an active portion thereof and an anchoring domain. The therapeutically effective amount comprises an amount of the fusion protein that results in a reduction of the quanitity of mucus in the respiratory tract after administration of the compound or composition when compared to the quantity of mucus present prior to administration of the compound or composition.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2010

DESCRIPTION (provided by applicant): Broad-spectrum prophylaxis and therapeutics for respiratory viral infections are highly desirable due to the immense socioeconomic burden imposed by the respiratory viruses. Human parainfluenza viruses (HPIV) represent a significant portion of respiratory viral disease. There are currently no approved treatments for the prevention or treatment of HPIV. The aims of this proposal are the first steps in a clinical development program to address this unmet medical need. The long-term objective of this project is to bring DAS181 into clinical trials in an HPIV indication. DAS181 is a recombinant fusion protein composed of a sialidase catalytic domain fused with an epithelium-anchoring sequence which functions by eliminating sialic acids on the airway epithelium. DAS181 is currently in clinical development for treatment of influenza virus (IFV) infection. IFVs and HPIVs share a common pathway of virus binding to sialic acids on the surface of cells as the initial step in infection. Since DAS181 works by inactivating sialic acid, the drug potentially confers very broad protection against any virus utilizing binding to sialic acid to gain entry into the cell. There are two specific aims of this proposal: first, to demonstrate the in vitro efficacy and pharmacodynamics of DAS181 against clinical isolates of HPIV and second, to demonstrate the in vivo efficacy of DAS181 against HPIV using a cotton rat model with DAS181 prophlyaxis and treatment. To establish the proof-of-principle in vitro, clinical isolates confirmed to be HPIV1, 2 or 3 will be obtained. At least 20 different clinical isolates will be established for testing sensitivity to DAS181. The ability of DAS181 to inhibit HPIV infection in LLC-MK cells will be evaluated. The susceptibility of various HPIV isolates to DAS181 will be compared by EC50 and EC90 values at an equal level of viral challenge. The potential anti- HPIV effect of DAS181 against clinical HPIV isolates will also be evaluated using the well-differentiated human airway epithelium culture (HAE). This model will allow the assessment of time of DAS181 exposure on the infection of HPIV. The cotton rat model of HPIV will be used to determine in vivo efficacy. Following the establishment of the model to determine the optimum infection of HPIV isolates, the efficacy of DAS181 will be evaluated in the prophylaxis, pre-HPIV inoculation model. Subsequent in vivo studies in cotton rats will define the time course of DAS181 treatment for existing HPIV infection. Accomplishing these two aims of defining pharmacological efficacy of DAS181 in HPIV infection will provide the rationale for engaging in pre-INS development, IND submission, and eventually the conduct of clinical trials in this indication. As DAS181 is already in a Phase I clinical trial for an influenza indication, the development path forward into an HPIV indication could be quite rapid upon this demonstration of potent activity against HPIV. PUBLIC HEALTH RELEVANCE: There is currently no treatment for human parainfluenza viral (HPIV) infection and no vaccine for prevention of infection. Yet HPIV represents a significant disease burden, especially for children, and represents a large unmet medical need. The proposed studies will establish Fludase(R), a novel recombinant fusion protein, as a potential drug for HPIV infections.


Moss R.B.,Nexbio, Inc. | Davey R.T.,National Institute of Allergy and Infectious Diseases | Fang F.,Nexbio, Inc.
Journal of Antimicrobial Chemotherapy | Year: 2010

The emergence of the 2009 H1N1 pandemic influenza A virus, as well as constant antigenic drift of seasonal influenza, underscores the remarkable versatility of this virus in adapting to the human population. While vaccines are the principal public health defence against influenza, rapid vaccine development can be a daunting task. Antiviral drugs offer the promise of inhibiting influenza regardless of its genetic variations. However, the rapid rise of resistance to several antivirals has highlighted the need for developing novel therapeutics with reduced drug resistance potential. In this review, we will summarize the effects of the currently licensed anti-influenza drugs as well as the candidates in development against the seasonal and the 2009 H1N1 pandemic influenza A virus with an emphasis on drug resistance. © The Author 2010. Published by Oxford University Press. Source

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