GAITHERSBURG, MD, United States
GAITHERSBURG, MD, United States
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Warren T.K.,U.S. Army | Warfield K.L.,U.S. Army | Warfield K.L.,Integrated Biotherapeutics, Inc. | Wells J.,U.S. Army | And 8 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

There exists an urgent need to develop licensed drugs and vaccines for the treatment or prevention of filovirus infections. FGI-103 is a low-molecular-weight compound that was discovered through an in vitro screening assay utilizing a variant of Zaire ebolavirus (ZEBOV) that expresses green fluorescent protein. In vitro analyses demonstrated that FGI-103 also exhibits antiviral activity against wild-type ZEBOV and Sudan ebolavirus, as well as Marburgvirus (MARV) strains Ci67 and Ravn. In vivo administration of FGI-103 as a single intraperitoneal dose of 10 mg/kg delivered 24 h after infection is sufficient to completely protect mice against a lethal challenge with a mouse-adapted strain of either ZEBOV or MARV-Ravn. In a murine model of ZEBOV infection, delivery of FGI-103 reduces viremia and the viral burden in kidney, liver, and spleen tissues and is associated with subdued and delayed proinflammatory cytokine responses and tissue pathology. Taken together, these results identify a promising antiviral therapeutic candidate for the treatment of filovirus infections. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Patent
Functional Genetics, Inc. | Date: 2011-06-13

The invention provides for inhibition of viral disease by the provision to a mammalian host of antibodies directed against an escort protein like Tsg101. These proteins appear on the surface of a cell, and thus can be bound by circulating antibodies thereto. By binding escort proteins on the cell surface, budding of viral particles is inhibited. The virus infects the initial cells, but cannot escape that cell to infect the body en masse.


Patent
Functional Genetics, Inc. | Date: 2010-05-11

The invention reflects enhanced antibody expression of an antibody of interest by cell lines transformed by random homozygous gene perturbation methods to either increase or decrease the expression pattern of a gene of the cell line other than the antibody of interest. The transformed cell line exhibits specific productivity rates, SPR, for the RHGP transformed cell liens of 1.5 or more, as compared with the antibody expressing cell line parents prior to transformation by RHGP. A knock out or anti-sense construct may be devised to reduce expression of the target gene, a promoter may be inserter to enhance expression of the target gene. The antibodies expressed by the transformed cell lines exhibit the binding properties of their parent cell lines prior to transformation with RHGP, and increase Total Volumetric Production of said antibody by said cells in a given volume.


Patent
Functional Genetics, Inc. | Date: 2010-05-10

A human gene, fg01, on chromosome 8, is identified, as well as a truncated form on chromosome 5. Upregulation appears to suppress the Alzheimers phenotype, (AB plaques and hyperphosphorylated tau tangles) which may address the onset of symptoms or progression of symptoms associated with AD. Screening methods are also set forth.


Patent
Functional Genetics, Inc. | Date: 2011-01-25

XMRV appears to be related to both prostate cancer if it infects a male germ cell and chronic fatigue syndrome in both sexes. (If the virus does not infect a germ cell). Prostate cancer cells exhibit TSG101 on the surface only upon infection with a virus like XMRV. Antibodies to TSG101 can be effective diagnostics to identify individuals with a predisposition to prostate. They can also be used in place of current diagnostics to confirm the presence of prostate cancer. TSG101 antibodies, when administered in vivo, exhibit the ability to reduce tumor size, suppress metastatic transformation and extend survival.


Patent
Functional Genetics, Inc. | Date: 2012-10-24

The present invention provides antibodies that bind to the C-terminal region of TSG101. The invention also provides these antibodies for use in the treatment of viral infections, including HIV and Ebola virus infection.


Patent
Functional Genetics, Inc. | Date: 2011-08-24

The invention provides for inhibition of viral disease by the provision to a mammalian host of antibodies directed against an escort protein like Tsg101. These proteins appear on the surface of a cell, and thus can be bound by circulating antibodies thereto. By binding escort proteins on the cell surface, budding of viral particles is inhibited. The virus infects the initial cells, but cannot escape that cell to infect the body en masse.


A method for identifying host genes and encoded proteins for potential targets for therapeutic intervention employs a Gene Search Vector that is either lentivirus or MMLV-based, and can be used to interrogate an entire cell genome without prior knowledge of the genomic sequence. This Random Homozygous Gene Perturbation (RUGP) technique is rapidly verifiable and is used to identify potential host targets for intervention for influenza, HIV and other viral infections. Using Thermal Assymetric Interlaced (TAIL)-PCR, the period for identification of promising targets is reduced from months to weeks or less. Specific targets including PTCH1, Robo1 and Nedd4 are reviewed in detail.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.88M | Year: 2010

DESCRIPTION (provided by applicant): Infection with influenza virus causes a highly contagious disease of the respiratory tract. Influenza represents a unique therapeutic challenge due to both seasonal antigen shift and drift. Conventional approaches for therapeutic targeting of influenza pathogens have consistently faced obstacles arising from the development of resistant strains and a lack of broad-spectrum application. The overall goal of this project is to develop broad- spectrum Host Oriented Therapeutic antibodies that are active against all strains of influenza including those that are resistant to current antiviral therapies. Phase I of this project has been successfully completed. Our original proposal centered upon a newly- developed approach, Random Homozygous Gene Perturbation (RHGP), which can simultaneously knockdown both copies of a target gene and identify those target knock-outs that are well-tolerated in normal cells but inhibit influenza infection. We applied RHGP to identify a set of host-oriented targets that prevent influenza killing of host cells and validate these targets. We further emphasized one particular pathway, based on the RHGP discovery of Nedd4 Binding Protein 2 (N4BP2) and WWP2, a member of Nedd4 family. This investigation allowed us to demonstrate that Nedd4 is exposed on the surface of influenza-infected cells but not on non-infected cells. This unique discovery positions us with an opportunity to develop a broad-spectrum inhibitor of influenza infection, which could act both as a therapeutic and prophylactic therapy to combat seasonal or pandemic forms of influenza. The specific aims of Phase II are to 1) Create human scFv libraries and screen the candidate antibodies using Nedd4 protein and the peptides. We will isolate approximately 200 different Nedd4-specific scFvs, from which we will select at least 10 different candidates that demonstrate immunoreactivity against a broad-spectrum of seasonal influenza variants and other potential pandemic variants. The leading ten scFv candidates will then be constructed into full-length human IgG1. 2) Evaluate the safety and antiviral activity of the antibody candidates to identify a lead candidate for IND-enabling studies through ADCC, CDC and direct antiviral activity. 3) Optimize the lead candidate to enable the nomination of a Clinical Candidate that has the greatest potential for becoming a successful IND. We believe the concept of selective targeting of influenza-infected cells has exciting prospects and that it is feasible to develop a therapeutic monoclonal antibody that is applicable to a broad spectrum of seasonal and pandemic influenza strains. PUBLIC HEALTH RELEVANCE: Conventional approaches for therapeutic targeting of the influenza virus have consistently faced obstacles arising from a high viral mutation rate and a lack of broad-spectrum application. The overall goal of this project is to develop broad-spectrum Host Oriented Therapeutic antibodies that target Nedd4, a molecule that is selectively exposed on the surface of influenza-infected cells. These antibodies are expected to be active against all strains of influenza, including those with resistance to current antiviral therapies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.79M | Year: 2010

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus (HIV-1) is a global threat to public health and poses an unprecedented challenge to drug development. HIV-1 drugs that directly target virus often fail due to rapid emergence of drug resistance. Functional Genetics (FGI) used a proprietary technology, Random Homozygous Gene Perturbation (RHGP) and discovered novel host gene targets that block HIV-1 infection without observable deleterious effect on cell survival. Unlike viral-targets, treatments relying on cellular targets are expected to retain broad spectrum efficacy against all HIV variants including drug-resistant viruses. In addition, by removing the selective pressure on the virus, host targeting circumvents drug resistance development. The identified targets in Phase I studies were validated using a siRNA approach and also shown to be commonly necessary for infection by both CXCR4 and CCR5 tropic HIV1 viruses. These results demonstrate the power of FGI proprietary RHGP technology to identify host targets(s) in human genome that block viral infection and at the same time are non-toxic. In the Phase II proposal, we will develop novel targeted intervention against HIV using monoclonal antibody therapeutics. We will focus on one particular host target, Robo1 , which is essential for the life cycle of HIV-1. To this end, we have discovered that Robo1 expression is activated in primary CD4+ T lymphocytes by HIV-1 infection. As a result, Robo1 uniquely appears on the surface of live, viral producing cells. Robo1 antibodies exhibited anti-HIV-1 activity in human PBMC assays. Robo1 thus can be targeted by monoclonal antibodies to block HIV life cycle and/or to eliminate infected cells via normal host defense mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC). We will conduct phage-based screening of human scFv libraries to identify antibody candidates that selectively recognize HIV-1 infected but not uninfected cells. These leading scFv candidates will be built out into full- length human IgG1 antibodies and using molecular evolution approach, the binding affinities of lead antibody candidates will be enhanced by several orders of magnitude. Their broad spectrum anti-viral abilities will then be evaluated including direct inhibition of viral replication and/or mediation of ADCC and CDC effects in vitro and efficacy in humanized mice. Antibody lead(s) will be further scrutinized through cell-based, animal-based and tissue cross-reactivity assays. Based on antiviral activities and iterative improvements, we will nominate a lead Robo1 antibody candidate for IND-enabling studies. We believe the concept of selective targeting of HIV- infected cells has exciting prospects and that it is feasible to develop a therapeutic monoclonal antibody against a broad spectrum of HIV isolates. PUBLIC HEALTH RELEVANCE: Most current AIDS drugs target the HIV virus and therefore enable the development of drug resistance through viral mutation. The Phase I project seeks to identify human host targets (as opposed to HIV virus targets) that will prevent the HIV virus from using the host's cellular mechanism for its life cycle. The overall goal of Phase II is to develop Host Oriented Therapeutic antibodies using targets identified from Phase I. These antibodies are expected to be active against all variants of HIV, including those with resistance to current antiviral therapies.

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