title: Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope.
abstract: Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue.
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA; Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
authors.forename: Luke N
authors.initials: LN
authors.lastname: Robinson
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Tharakaraman
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Rowley
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore.
authors.forename: Vivian V
authors.initials: VV
authors.lastname: Costa
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
authors.forename: Kuan Rong
authors.initials: KR
authors.lastname: Chan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Yee Hwa
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore.
authors.forename: Li Ching
authors.initials: LC
authors.lastname: Ong
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
authors.forename: Hwee Cheng
authors.initials: HC
authors.lastname: Tan
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Tyree
authors.initials: T
authors.lastname: Koch
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
authors.forename: David
authors.initials: D
authors.lastname: Cain
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kirloskar
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Chong Wai
authors.initials: CW
authors.lastname: Liew
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Tissire
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Boopathy
authors.initials: B
authors.lastname: Ramakrishnan
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Myette
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Babcock
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA.
authors.forename: V
authors.initials: V
authors.lastname: Sasisekharan
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Microbiology, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 3, Singapore 117545.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Biology, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139, USA.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Julien
authors.initials: J
authors.lastname: Lescar
authors.affiliation: Visterra Inc., One Kendall Square, Suite B3301, Cambridge, MA 02139, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Shriver
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore; Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139; USA; Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore. Electronic address: rams@mit.edu.
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000737:chemistry*; D003715:Dengue / Q000276:immunology / Q000628:therapy* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D016056:Immunodominant Epitopes / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010587:Phagocytosis; D015202:Protein Engineering; D011961:Receptors, Fc / Q000276:immunology; D016415:Sequence Alignment
chemical_list: D057134:Antibodies, Neutralizing; D016056:Immunodominant Epitopes; D011961:Receptors, Fc