Structure-guided redesign of monoclonal antibodies targeting conserved filovirus epitopes

Period of Performance: 07/01/2016 - 06/30/2017

$284K

Phase 1 SBIR

Recipient Firm

Integrated Biotherapeutics, Inc.
ROCKVILLE, MD 20850
Principal Investigator

Abstract

Project SummaryThe Filoviridae family consists of multiple phylogenetically diverse species including five speciesof ebolavirus and a single marburgvirus species with Marburg and Ravn viruses. While Ebolavirus (EBOV; formerly known as Zaire) has caused the majority of filovirus hemorrhagic feverepidemics including the 2014 outbreak in West Africa, other members of Filoviridae have alsocaused human epidemics including 12, 8, and 2 outbreaks of Marburg (MARV), Sudan (SUDV),and Bundibugyo (BDBV) viruses, respectively. It is impossible to predict the species or locationof future outbreaks, thus a broadly protective therapeutic would be highly desirable. However,current immunotherapeutic candidates including ZMapp are species-specific. The objective of thisproject is to develop broadly neutralizing pan-filovirus antibodies with protection against the majorfilovirus species.Integrated Biotherapeutics Inc. (IBT) has recently developed a set of pan-ebolavirus monoclonalantibodies that target novel conserved epitopes within filovirus glycoproteins (GP). Two of thesemAbs bind with low affinity to MARV, which is phylogenetically distant and has only 28% sequenceidentity within GP with ebolavirus species. Visterra Inc, has developed a framework to computethe inter-residue atomic interactions between interacting amino acid pairs of an antigen-antibodyinterface. This technology enables in silico optimization of CDRs to enhance amino acidinteraction fitness at the paratope-epitope interface to drive increased affinity or widening of thebreadth of reactivity. Using this approach a Dengue virus mAb was engineered to achieve 13000fold increased binding to DENV-IV and a pan-influenza mAb was created that is now in clinicaldevelopment. In this proposal, IBT and Visterra are partnering to use this novel approach tocreate effective pan-filovirus mAbs by expanding the breadth of reactivity of two antibodies thatbind with high affinity to novel pan-ebolavirus epitopes within the core GP1 and the fusion loop ofall ebolavirus species but show low affinity towards MARV. In Specific Aim 1, these two mAbswill be subjected to an iterative structure-based engineering to achieve strong binding to Marburgglycoprotein without loss of ebolavirus reactivity. Up to 10 derivatives with broad cross reactivityto all filoviruses will be selected for further characterization and efficacy testing. In Aim 2, theselected redesigned mAbs will be thoroughly characterized for cross-species binding, affinity, aswell as neutralization. The most potent antibodies (or cocktails) will be evaluated in mouse modelsof EBOV, SUDV, and MARV.If the Phase I is successful, a Phase II project is envisioned in which the efficacy of the candidateswill be tested in nonhuman primate models of EBOV, SUDV, MARV, and BDBV with the ultimategoal of advancing the product towards clinical development.