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Structure-guided redesign of monoclonal antibodies targeting conserved filovirus epitopes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AI124765-01A1
Agency Tracking Number: R43AI124765
Amount: $284,365.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: R
Solicitation Number: PA15-269
Solicitation Year: 2015
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-07-01
Award End Date (Contract End Date): 2018-06-30
Small Business Information
Gaithersburg, MD 20878-1757
United States
DUNS: 601000750
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (240) 454-8940
Business Contact
Phone: (301) 454-8940
Research Institution

Project Summary
The Filoviridae family consists of multiple phylogenetically diverse species including five species
of ebolavirus and a single marburgvirus species with Marburg and Ravn viruses While Ebola
virus EBOV formerly known as Zaire has caused the majority of filovirus hemorrhagic fever
epidemics including the outbreak in West Africa other members of Filoviridae have also
caused human epidemics including and outbreaks of Marburg MARV Sudan SUDV
and Bundibugyo BDBV viruses respectively It is impossible to predict the species or location
of future outbreaks thus a broadly protective therapeutic would be highly desirable However
current immunotherapeutic candidates including ZMapp are species specific The objective of this
project is to develop broadly neutralizing pan filovirus antibodies with protection against the major
filovirus species
Integrated Biotherapeutics Inc IBT has recently developed a set of pan ebolavirus monoclonal
antibodies that target novel conserved epitopes within filovirus glycoproteins GP Two of these
mAbs bind with low affinity to MARV which is phylogenetically distant and has only sequence
identity within GP with ebolavirus species Visterra Inc has developed a framework to compute
the inter residue atomic interactions between interacting amino acid pairs of an antigen antibody
interface This technology enables in silico optimization of CDRs to enhance amino acid
interaction fitness at the paratope epitope interface to drive increased affinity or widening of the
breadth of reactivity Using this approach a Dengue virus mAb was engineered to achieve
fold increased binding to DENV IV and a pan influenza mAb was created that is now in clinical
development In this proposal IBT and Visterra are partnering to use this novel approach to
create effective pan filovirus mAbs by expanding the breadth of reactivity of two antibodies that
bind with high affinity to novel pan ebolavirus epitopes within the core GP and the fusion loop of
all ebolavirus species but show low affinity towards MARV In Specific Aim these two mAbs
will be subjected to an iterative structure based engineering to achieve strong binding to Marburg
glycoprotein without loss of ebolavirus reactivity Up to derivatives with broad cross reactivity
to all filoviruses will be selected for further characterization and efficacy testing In Aim the
selected redesigned mAbs will be thoroughly characterized for cross species binding affinity as
well as neutralization The most potent antibodies or cocktails will be evaluated in mouse models
If the Phase I is successful a Phase II project is envisioned in which the efficacy of the candidates
will be tested in nonhuman primate models of EBOV SUDV MARV and BDBV with the ultimate
goal of advancing the product towards clinical development Filoviruses including Ebola virus are among the deadliest viruses known to humans The
success of ZMapp has demonstrated that antibodies are effective therapeutics for filoviruses
However ZMapp is only effective against the Zaire species that caused the outbreak The
objective of this SBIR project is to redesign a set of Ebola virus therapeutic antibodies to acquire
the ability to neutralize all members of filovirus family Such a product would be effective against
all major and pathogenic species of filoviruses

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

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