Structure-guided redesign of monoclonal antibodies targeting conserved filovirus epitopes

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 of EBOV SUDV and MARV 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