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Monoclonal antibodies targeting novel sites of vulnerability in marburg virus glycoprotein

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI147929-01
Agency Tracking Number: R41AI147929
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-07-12
Award End Date (Contract End Date): 2021-06-30
Small Business Information
21 FIRST FIELD RD STE 100, Gaithersburg, MD, 20878-1757
DUNS: 601000750
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 M AMAN
 (240) 454-8940
 javad@integratedbiotherapeutics.com
Business Contact
 M. JAVAD AMAN
Phone: (240) 454-8940
Email: javad@integratedbiotherapeutics.com
Research Institution
 UNIVERSITY OF MARYLAND BALTIMORE
 620 W LEXINGTON ST, 4TH FL
BALTIMORE, MD, 21201-1508
 Nonprofit college or university
Abstract
Filovirusesconsisting of two major virus families including the ebolaviruses and marburgvirusesMARV and RAVVcause periodic outbreaks of severe viral hemorrhagic fever with mortality rates as high asSince it is difficult to predict the species that would dominate future outbreaksdevelopment of broadly protective therapeutics to prevent and manage future filovirus outbreaks is of high priorityIn sharp contrast to the recent major breakthrough reported by us and others on isolation and development of a number of effective and broadly neutralizing mAbsbNAbsfor ebolavirusesonly a single class of mAbs against marburgvirus GP has been described that target the same epitope within the receptor binding siteRBSof MARV and RAVV GPMRis the only MARV RAVV GP RBS specific monoclonal antibodymAbthat has been shown to protect against MARV infection in nonhuman primatesNHPshowever at very high dosesdoses ofmg kg eachThusit is important to identify novel sites of vulnerability in MARV RAVV GP and develop more potent immunotherapeutics against these deadly virusesHaving a variety of bNAbs will allow the design of therapeutic cocktails containing multiple mAbs targeting distinct epitopesa strategy that has been shown tobe extremely effective against ebolaviruses to combat possible virus escape variantsThere has been a long standing and productive collaboration between Integrated BioTherapeuticsIBTand University of MarylandUMDthat has recently resulted in highly potent ebolavirus bNAbs with remarkable efficacy in animal models including nonhuman primateNHPand ferret models of EBOVSUDVand BDBV infectionZhao et alCelleLatelyusing a prime boost immunization strategy in NHPs combined with a novel memory B cell counter screening with engineered GP mutantswe were able to isolatefor the first timea group of highly potent MARV RAVV bNAbs that target a new class of epitopes distinct from the RBS binding MR seriesIn this STTR applicationwe aim to address the major challenge of MARV immunotherapy by developing top lead candidate marburgvirus therapeutic antibodies derived from these novel MARV RAVV bNAbsWe will iselectlead therapeutic mAbs among the current bNAb candidatesiioptimize the lead mAbs and select for the final humanized optimized candidate by state of the art computer aided optimization and efficacy study in a stringent guinea pig model of MARV infectionand iiiidentify the final lead mAbor cocktailby testing the efficacy of candidates in NHP model of MARV infectionUpon completion of the proposed Phase I project we envision a Phase II project with the following objectivesiexpand the efficacy studies to RAVV and dose optimization in NHPsiidevelop manufacturing cell lines in CHO cellsiiidevelop bioanalytical methods for product release and PKand ivconduct safety and tissue cross reactivity studies using the GLP grade clinical candidateIf successfulwe anticipate further development of the product under DoD or BARDA funding and approval under FDA Animal Rule Filoviruses are among the deadliest pathogens known to humansThe Ebola virus disease outbreak in West Africacaused by the Zaire Ebola virusresulted in overcases anddeathsIn addition to Ebola virusa related filovirus called Marburg has caused five outbreaks in the pastyears with high fatality ratesThis proposal is aimed at developing effective immunotherapeutics against Marburg virusWe have generated several antibody drug candidates that protect against Marburg infectionUnder this proposal we will further characterize these drug candidates and test their efficacy in mice and nonhuman primatesThis studyif successfulwill set the stage for clinical development of an effective therapeutic for human use

* Information listed above is at the time of submission. *

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